Liver x receptor (lxr) modulators

ABSTRACT

Described herein are liver X receptor (LXR) modulators and methods of utilizing LXR modulators in the treatment of LXR-associated diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.17/552,287, filed Dec. 15, 2021, which is a continuation of U.S.application Ser. No. 17/315,035, filed May 7, 2021, now abandoned, whichis a continuation of U.S. application Ser. No. 16/269,444, filed Feb. 6,2019, now U.S. Pat. No. 11,034,657, issued Jun. 15, 2021, which is acontinuation of U.S. application Ser. No. 16/054,884, filed Aug. 3,2018, now U.S. Pat. No. 10,246,419, issued Apr. 2, 2019, which is acontinuation of U.S. application Ser. No. 14/916,275, filed Mar. 3,2016, now U.S. Pat. No. 10,047,055, issued Aug. 14, 2018, which is aNational Phase application of International Application No.PCT/US2014/054043, filed Sep. 4, 2014, which claims benefit fromProvisional Application No. 61/873,755, filed Sep. 4, 2013, which areherein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Liver X receptor (LXR), first described by Willy, P. J., et al. (“LXR, anuclear receptor that defines a distinct retinoid response pathway,”Genes & Development 9:1033-1045 (Cold Spring Harbor Laboratory Press)),is a member of the nuclear hormone superfamily and consists of twosubtypes, LXR alpha and LXR beta. LXR modulates a variety ofphysiological responses including inflammation in various tissues andcell types, regulation of cholesterol absorption, cholesterolelimination (bile acid synthesis), and transport of cholesterol fromperipheral tissues via plasma lipoproteins to the liver. LXR alsoregulates genes involved in glucose metabolism, cholesterol metabolismin the brain and apolipoproteins such as ApoE and its isoforms, that areimplicated in cellular differentiation and apopotosis, inflammation,neurodegenerative disease, and infectious diseases (Geyeregger, R. etal., Cell. Mol. Life Sci. 2006, 63:524-539). LXR also regulates genes,including ApoE, in melanoma cells and melanocytes (Lim, K. M., et al., JInvest Dermatol. (2013) 133(4):1063-71) and thus is also a therapeutictarget for treatment of certain types of cancers.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula I, IA, IB, IC, II, IIA, orIIB, pharmaceutical compositions that include such compounds, andmethods of use thereof, for modulating LXR. In one aspect is theadministration of at least one LXR modulator described herein to amammal in the treatment of diseases, disorders or conditions that wouldbenefit from LXR modulation.

In one aspect is a compound of Formula (I):

wherein:

A and B are each nitrogen, wherein A and B are bonded together to form afive-membered heteroaryl ring;

L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₄ is aryl or heteroaryl; wherein aryl or heteroaryl is substituted withat least one R₁₁;

each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl,or heteroaryl;

each R₉ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₀ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-4;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula I wherein R₄ is aryl. Inanother embodiment is a compound of Formula I wherein R₄ is phenylsubstituted with at least one R₁₁. In a further embodiment is a compoundof Formula I wherein R₄ is phenyl substituted with one R₁₁, R₁₁ is—SO₂R₁₀, and R₁₀ is C₁-C₆alkyl. In a further embodiment is a compound ofFormula I wherein L₁ is a bond. In yet a further embodiment is acompound of Formula I wherein R₁ is C₁-C₆alkyl. In another embodiment isa compound of Formula I wherein R₁ is C₂-C₆alkenyl. In anotherembodiment is a compound of Formula I wherein R₁ is C₁-C₆haloalkyl. Inanother embodiment is a compound of Formula I wherein R₁ is —CF₃. Inanother embodiment is a compound of Formula I wherein R₁ is —C(═O)R₈. Inanother embodiment is a compound of Formula I wherein R₁ is —C(═O)R₈,and R₈ is C₁-C₆alkyl. In another embodiment is a compound of Formula Iwherein R₁ is C(═O)N(R₉)₂. In another embodiment of the aforementionedembodiments is a compound of Formula I wherein R₂ is C₁-C₆alkyl. Inanother embodiment of the aforementioned embodiments is a compound ofFormula I wherein R₂ is isobutyl. In another embodiment of theaforementioned embodiments is a compound of Formula I wherein R₃ ishydrogen. In another embodiment of the aforementioned embodiments is acompound of Formula I wherein R₃ is halogen.

In another aspect is a compound of Formula (II):

wherein:

X is —O—, —S—, or —C(R₆)═C(R₆)—;

L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₄ is aryl or heteroaryl; wherein aryl or heteroaryl is substituted withat least one R₁₁;

each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

each R₆ is independently hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl;

R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl,or heteroaryl;

each R₉ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₀ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-2;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula II wherein L₁ is a bond.In another embodiment is a compound of Formula II wherein L₁ isC₁-C₆alkyl; and R₁ is —OH. In another embodiment is a compound ofFormula II wherein L₁ is —CH₂—. In a further embodiment is a compound ofFormula II wherein R₁ is —C(═O)OR₈, and R₈ is C₁-C₆alkyl orC₁-C₆heteroalkyl. In a further embodiment is a compound of Formula IIwherein L₂ is C₁-C₆alkyl. In a further embodiment is a compound ofFormula II wherein R₂ is H. In another embodiment of the aforementionedembodiments is a compound of Formula II wherein R₄ is phenyl substitutedwith one R₁₁. In another embodiment of the aforementioned embodiments isa compound of Formula II wherein R₄ is phenyl substituted with one R₁₁,R₁₁ is —SO₂R₁₀, and R₁₀ is C₁-C₆alkyl. In another embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with at least two R₁₁. In another embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with at least two R₁₁ and each R₁₁ is independentlyhalogen, optionally substituted C₁-C₆alkyl, —SO₂R₁₀, —NR₁₀SO₂R₁₀, or—SO₂N(R₁₀)₂. In another embodiment of the aforementioned embodiments isa compound of Formula II wherein n is 0. In another embodiment of theaforementioned embodiments is a compound of Formula II wherein R₃ ishydrogen. In another embodiment of the aforementioned embodiments is acompound of Formula II wherein R₃ is halogen. In another embodiment ofthe aforementioned embodiments is a compound of Formula II wherein X is—O—. In another embodiment of the aforementioned embodiments is acompound of Formula II wherein X is —S—. In another embodiment of theaforementioned embodiments is a compound of Formula II wherein X is—CH═CH—.

In another aspect is a pharmaceutical composition comprising apharmaceutically acceptable diluent, excipient, carrier or binder and acompound of Formula I, IA, IB, IC, II, IIA, or IIB, or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

In another aspect is a method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound of Formula I, IA, IB, IC, II,IIA, or IIB, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound of Formula I, IA, IB, IC, II,IIA, or IIB, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof,wherein the disease, disorder or condition in a mammal is increasedlipid levels, increased cholesterol levels, low HDL-cholesterol, highLDL-cholesterol, atherosclerotic diseases, diabetes, non-insulindependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis,inflammatory diseases, infectious diseases, skin diseases, colitis,pancreatitis, cholestasis of the liver, fibrosis of the liver,psoriasis, Alzheimer's disease, Parkinson's disease, impaired/improvablecognitive function, HIV, cancer including metastatic cancer andmetastatic melanoma, and age related forms of macular degeneration (wetand dry forms).

In some embodiments is a method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound of Formula I, IA, IB, IC, II,IIA, or IIB, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof,wherein the disease, disorder or condition in a mammal is cancer. Insome embodiments the cancer is malignant melanoma. In some embodimentsthe ApoE levels are reduced in the cancer. In some embodiments themethod further comprises the administration of a second therapeuticagent. In some embodiments the second therapeutic agent is a BRAFinhibitor. In some embodiments the BRAF inhibitor is selected fromPDC-4032, GSK2118436, and PLX-3603. In some embodiments the secondtherapeutic agent is sunitinib malate, sorafenib tosylate, imatinibmesylate, or nilotinib hydrochloride monohydrate; or a combinationthereof. In some embodiments of the aforementioned embodiments themammal is a human.

In some embodiments is a method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound of Formula I, IA, IB, IC, II,IIA, or IIB, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof,wherein the disease, disorder or condition in a mammal is Alzheimer'sdisease.

In some embodiments is a method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound of Formula I, IA, IB, IC, II,IIA, or IIB, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof,wherein the disease, disorder or condition in a mammal is Parkinson'sdisease.

In another embodiment is the use of a compound of Formula I, IA, IB, IC,II, IIA, or IIB in the manufacture of a medicament for the treatment ofa disease, disorder, or condition that would benefit from LXR modulation(such as any of the methods described herein). In another embodiment isa compound of Formula I, IA, IB, IC, II, IIA, or IIB for use in the anyof the methods described herein. In another embodiment is the use of aLXR modulator in the manufacture of a medicament for use in thetreatment of a disease, disorder or condition in a mammal, wherein thedisease, disorder or condition in a mammal is increased lipid levels,increased cholesterol levels, low HDL-cholesterol, high LDL-cholesterol,atherosclerotic diseases, diabetes, non-insulin dependent diabetesmellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatorydiseases, infectious diseases, skin diseases, colitis, pancreatitis,cholestasis of the liver, fibrosis of the liver, psoriasis, Alzheimer'sdisease, Parkinson's disease, impaired/improvable cognitive function,HIV, cancer including metastatic cancer and metastatic melanoma, acutemacular degeneration, and age related forms of macular degeneration (wetand dry forms). In another embodiment is the use of a LXR modulator anda second therapeutic agent in the manufacture of a medicament for use inthe treatment of a disease, disorder or condition in a mammal, whereinthe disease, disorder or condition in a mammal is increased lipidlevels, increased cholesterol levels, low HDL-cholesterol, highLDL-cholesterol, atherosclerotic diseases, diabetes, non-insulindependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis,inflammatory diseases, infectious diseases, skin diseases, colitis,pancreatitis, cholestasis of the liver, fibrosis of the liver,psoriasis, Alzheimer's disease, Parkinson's disease, impaired/improvablecognitive function, HIV, cancer including metastatic cancer andmetastatic melanoma, and age related forms of macular degeneration (wetand dry forms).

In another aspect is a method of modulating LXR activity comprisingcontacting LXR, or portion thereof, with a compound of Formula I, IA,IB, IC, II, IIA, or IIB, or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows ABCA1 gene expression analyzed by QT-PCR for Compound 4 asoutlined in Example 13.

FIG. 2 shows ABCG1 gene expression analyzed by QT-PCR for Compound 4 asoutlined in Example 13.

FIG. 3 shows IL1β gene expression analyzed by QT-PCR for Compound 4 asoutlined in Example 14.

FIG. 4 shows αSyn gene expression analyzed by QT-PCR for Compound 4 asoutlined in Example 15.

DETAILED DESCRIPTION OF THE INVENTION Metastatic Melanoma

Expression levels of certain micro RNAs (miRNAs), including miRNA-1908,miRNA-199a-5p and miRNA-199a-3p and ApoE, including ApoE3 and ApoE4,correlate with the progression of malignant melanomas and metastaticdisease as well as frequencies in other cancers (Tavazoie, S. F., etal., Cell (2012) 151:1-15). The discovery that the three miRNAscombinatorially target metastatic melanoma suppression establishes theirpotential as melanoma biomarkers. In particular, melanoma cell-secretedApoE suppresses metastatic invasion and endothelial recruitment.Cancer-derived ApoE has been directly linked to modulation of metastaticangiogenesis in melanoma cells as well as in other cancer types. Agentsthat increase the expression of ApoE are therefore potential therapeuticagents for suppressing endothelial migration and tumor invasion and forthe treatment of malignant metastatic melanoma and other cancers. LXRagonists have been shown to regulate ApoE in primary human melanomacells (Lim, K. M., et al., J Invest Dermatol. (2013) 133(4):1063-71),identifying ApoE as a LXR target gene in melanoma cells and inmelanocytes. As ApoE up-regulation is associated with tumor suppressionin melanoma cells, LXR agonists should be effective in therapeuticintervention and prevention of metastatic melanoma and other cancersassociated with ApoE-related angiogenesis. In some embodiments describedherein are methods to treat cancer patients using LXR agonists who haveabnormal levels of apolipoprotein E (ApoE), including lower expressionlevels of ApoE and its isoforms using a compound of Formula I, IA, IB,IC, II, IIA, or IIB. In some embodiments described herein are methods totreat metastatic melanoma using a compound of Formula I, IA, IB, IC, II,IIA, or IIB.

Alzheimer's Disease, Neurodegenerative Disorders, Traumatic Brain Injury

LXRs are key regulators of genes that inhibit the inflammatory responsein multiple cell types, including microglial cells in the CNS. LXR hasbeen implicated in playing a critical role in the removal of accumulatedamyloid beta in the brain. In particular, LXR agonists increase theexpression of the ATP-binding cassette transporter ABCA1 (a cholesteroltransporter), to facilitate the lipidation of ApoE and directly promotemicroglia-mediated clearance of Aβ.

Data from in vitro and in vivo studies (Pfrieger, F. W. et al., Science(2001); 294:1354-7; Lazo, J. S. et al., J Biol Chem. (2005) 280:4079-88)validate the role of ApoE in facilitating the proteolytic clearance ofsoluble Aβ from the brain. The capacity of ApoE to promote Aβdegradation is isoform specific and dependent upon lipidation status.ApoE is lipidated by ABCA1 in multiple cell types, transferring bothphospholipids and cholesterol to ApoA-I in the periphery, and bothApoA-I and ApoE in brain. In this manner, lipidated ApoE as well asApoA-I transport cholesterol and other lipids from astrocytes. Thisprocess is necessary to maintain synaptic plasticity and neuronalremodeling in a healthy brain.

Three independent studies have reported that global deletion of ABCA1 inAPP transgenic mice results in increased levels of amyloid depositionwithout a significant effect on Aβ generation. Studies with the LXRagonists in APP-expressing mice show LXR agonism decreases Aβ levels,and this decrease is correlated with increased ApoA-I and ApoE levels inthe brains of treated animals (Koldamova R. et al., Mol Neurodegener(2007); 2:20). Using the same LXR agonist in a Tg2576 mouse model ofAlzheimer's disease, researchers have shown a pronounced improvement incognitive performance (Jacobsen J. S., et al., Mol Cell Neurosci. (2007)34:621-8).

The outcomes of these studies strongly suggest that ABCA1 and LXRregulate ApoE and ApoA-I lipidation, which in turn impacts Aβaggregation and allows for Aβ clearance and that LXR agonists should beeffective in treating neurodegenerative disorders such as Alzheimer'sdisease. In some embodiments described herein are methods to treatAlzheimer's disease using a compound of Formula I, IA, IB, IC, II, IIA,or IIB.

Parkinson's Disease

LXRs have been shown to play an important role in the CNS both inreducing inflammation in microglia and astrocytes and in effecting Abetaclearance with potential implications in the treatment of Parkinson'sdisease. Recent data show that LXR plays a role in the formation ofsuperficial cortical layers and migration of later-born neurons inembryonic mice. LXR agonists have a positive therapeutic effect ondopaminergic neurons in the substantia nigra in a MPTP-induced rodentmodel of Parkinson's disease where the MPTP-induced loss of dopaminergicneurons was significantly reduced in the mice treated with the LXRagonist relative to vehicle-treated animals (Gustafsson, J. A.; Proc.Natl. Acad. Sci. U.S.A. (2012) 109:13112-13117). LXR agonist treatmentalso resulted in an attenuation of the increase in GFAP-positive cellsin the substantia nigra pars compacta. Based on the above studies andother data in the literature, it is likely that LXR plays a key role inthe pathology of Parkinson's disease. Thus, selective LXR agonists withrequisite brain distribution should offer a novel therapeutic forParkinson's disease. In some embodiments described herein are methods totreat Parkinson's disease using a compound of Formula I, IA, IB, IC, II,IIA, or IIB.

Age-Related Macular Degeneration (AMD) Wet and Dry Forms

LXR pathways that have been studied in the CNS, such as regulation ofABC transporters and apolipoproteins such as ApoE and isoforms, are alsopertinent in the retinal cells and implicated in the pathology of AMD,both wet and dry. In retinal pigment epithelium cells, both primary andimmortalized, LXR agonists and modulators induce the expression of ABCA1and ApoE, target genes implicated in the pathology of AMD (Ishida,Journal of Lipid Research (2004) 45: 267-271). In mouse models of AMD,non-selective LXR agonists have been shown to provide beneficial effectson AMD progression (Sene, Cell Metabolism, 2013, 17: 549-561). Thus,selective LXR agonists and modulators should have a therapeutic benefitin the treatment of both wet and dry forms of AMD, a diseasecharacterized by abnormal cholesterol signaling and inflammatoryconditions.

Definitions

In the context of this disclosure, a number of terms shall be utilized.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of an LXR modulator that, when administered to a mammal inneed, is effective to at least partially ameliorate or to at leastpartially prevent diseases, disorders or conditions described herein.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “modulate” encompasses either a decrease or an increase inactivity or expression depending on the target molecule. For example, aTIMP1 modulator is considered to modulate the expression of TIMP1 if thepresence of such TIMP1 modulator results in an increase or decrease inTIMP1 expression.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The terms “induce” or “induction” of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2,TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn,or decorin expression refer to an increase, induction, or otherwiseaugmentation of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR,CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, or decorin mRNAand/or protein expression. The increase, induction, or augmentation canbe measured by one of the assays provided herein. Induction of TIMP1,ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, or decorin expression does not necessarilyindicate maximal expression of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2,TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn,or decorin. An increase in TIMP1, ABCA12, or decorin expression can be,for example, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%or more. In one embodiment, induction is measured by comparing TIMP1,ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, or decorin mRNA expression levels fromuntreated cells to that of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1,GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, ordecorin mRNA expression levels from LXR modulator-treated cells.

The terms “inhibit” or “inhibition” of TNFα, MMP1, MMP3, or IL-8expression refer to a reduction, inhibition, or otherwise diminution ofTNFα, MMP1, MMP3, or IL-8 mRNA and/or protein expression. The reduction,inhibition, or diminution of binding can be measured by one of theassays provided herein. Inhibition of TNFα, MMP1, MMP3, or IL-8expression does not necessarily indicate a complete negation of TNFα,MMP1, MMP3, or IL-8 expression. A reduction in expression can be, forexample, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ormore. In one embodiment, inhibition is measured by comparing TNFα, MMP1,MMP3, or IL-8 mRNA expression levels from untreated cells to that ofTNFα, MMP1, MMP3, or IL-8 mRNA expression levels from LXRmodulator-treated cells.

“Liver X receptor” or “LXR” refers to both LXRα and LXRβ, and variants,isoforms, and active fragments thereof. LXRβ is ubiquitously expressed,while LXRα expression is limited to liver, kidney, intestine, spleen,adipose tissue, macrophages, skeletal muscle, and skin. RepresentativeGenBank® accession numbers for LXRα sequences include the following:human (Homo sapiens, Q 13133), mouse (Mus musculus, Q9Z0Y9), rat (Rattusnorvegicus, Q62685), cow (Bos taurus, Q5E9B6), pig (Sus scrofa,AAY43056), chicken (Gallus gallus, AAM90897). Representative GenBank®accession numbers for LXRβ include the following: human (Homo sapiens,P55055), mouse (Mus musculus, Q60644), rat (Rattus norvegicus, Q62755),cow (Bos taurus, Q5BIS6).

The term “mammal” refers to a human, a non-human primate, canine,feline, bovine, ovine, porcine, murine, or other veterinary orlaboratory mammal. Those skilled in the art recognize that a therapywhich reduces the severity of a pathology in one species of mammal ispredictive of the effect of the therapy on another species of mammal.

“Proinflammatory cytokine” as used herein refers to any cytokine thatcan activate cytotoxic, inflammatory, or delayed hypersensitivityreactions. Exemplary proinflammatory cytokines include colonystimulating factors (CSFs), for example granulocyte-macrophage CSF,granulocyte CSF, erythropoietin; transforming growth factors (TGFs), forexample TGFβ; interferons (IFNs), for example IFNα, IFNβ, IFNγ;interleukins (ILs), for example IL-1α, IL-1β, IL-3, IL-6, IL-7, IL-8,IL-9, IL-11, IL-12, IL-15; tumor necrosis factors (TNFs), for exampleTNFα, TNFβ; adherence proteins, for example intracellular adhesionmolecule (ICAM), vascular cell adhesion molecule (VCAM); growth factors,for example leukemia inhibitory factor (LIF), macrophagemigration-inhibiting factor (MIF), epidermal growth factor (EGF),platelet-derived growth factor (PDGF), fibroblast growth factor (FGF),insulin-like growth factor (IGF), nerve growth factor (NGF), B-cellgrowth factor (BCGF); chemokines, for example monocyte chemoattractantproteins (MCP-1, MCP-2, MCP-3), macrophage inflammatory protein (MIP),growth-related oncogene, gamma interferon-inducible protein;leukotrienes, for example leukotriene B₄, leukotrine D₄; vasoactivefactors, for example histamine, bradykinin, platelet activating factor(PAF); prostaglandins, for example prostaglandin E₂.

LXR Modulators

LXR modulators contemplated for use in the compositions and methodsdescribed herein are compounds with LXRα and/or LXRβ modulatoractivities. The term “LXR modulator” includes LXRα and/or LXRβ agonists,antagonists and tissue selective LXR modulators, as well as other agentsthat induce the expression and/or protein levels of LXRs in cells.

Preferred compounds will be LXR modulators with LXRα and/or LXRβmodulator activities. Preferred LXR modulators are LXR activators. Theterm “LXR activator” or “activator of the LXR” includes LXRα and/or LXRβagonists, partial agonists and tissue selective LXR modulators, as wellas other agents that induce the expression and/or protein levels of LXRsin the cells.

In one embodiment is a compound of Formula (I):

wherein:

A and B are each nitrogen, wherein A and B are bonded together to form afive-membered heteroaryl ring;

L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₄ is aryl or heteroaryl; wherein aryl or heteroaryl is substituted withat least one R₁₁;

each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl,or heteroaryl;

each R₉ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₀ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-4;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (IA):

wherein:

L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₄ is aryl or heteroaryl; wherein aryl or heteroaryl is substituted withat least one R₁₁;

each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl,or heteroaryl;

each R₉ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₀ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-4;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In some embodiments, “optionally substituted” means optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromhalo, cyano, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, amino, C₁-C₄ alkylamino, and di(C₁-C₄alkyl)amino.

In some embodiments is a compound of Formula IA wherein R₄ is heteroarylsubstituted with at least one R₁₁. In some embodiments is a compound ofFormula IA wherein R₄ is aryl substituted with at least one R₁₁. In afurther embodiment is a compound of Formula IA wherein R₄ is phenylsubstituted with at least one R₁₁. In a further embodiment is a compoundof Formula IA wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl. In a further embodiment is a compound of FormulaIA wherein R₄ is phenyl substituted with at least one R₁₁ and each R₁₁is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN, —C(═O)R₁₀,—C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆heteroalkyl, or optionally substituted —C₁-C₆alkyl-aryl. In afurther embodiment is a compound of Formula IA wherein R₄ is phenylsubstituted with at least one R₁₁ and each R₁₁ is independently halogen,—C(═O)R₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, or optionally substituted C₁-C₆alkyl. In a furtherembodiment is a compound of Formula IA wherein R₄ is phenyl substitutedwith at least one R₁₁ and each R₁₁ is independently halogen, —SO₂R₁₀, oroptionally substituted C₁-C₆alkyl. In a further embodiment is a compoundof Formula IA wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently —SO₂R₁₀ or optionally substituted C₁-C₆alkyl.In a further embodiment is a compound of Formula IA wherein R₄ is phenylsubstituted with at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ oroptionally substituted C₁-C₆alkyl, and R₁₋ is C₁-C₆alkyl. In a furtherembodiment is a compound of Formula IA wherein R₄ is phenyl substitutedwith at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ or optionallysubstituted C₁-C₆alkyl, and R₁₁ is CH₃. In some embodiments is acompound of Formula IA wherein R₄ is aryl substituted with one R₁₁. Insome embodiments is a compound of Formula IA wherein R₄ is arylsubstituted with two R₁₁. In some embodiments is a compound of FormulaIA wherein R₄ is aryl substituted with three R₁₁. In further embodimentsis a compound of Formula IA wherein R₄ is phenyl substituted with oneR₁₁. In further embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with two R₁₁. In further embodiments is a compound ofFormula IA wherein R₄ is phenyl substituted with three R₁₁. In someembodiments is a compound of Formula IA wherein R₄ is heteroarylsubstituted with one R₁₁. In some embodiments is a compound of FormulaIA wherein R₄ is heteroaryl substituted with two R₁₁. In someembodiments is a compound of Formula IA wherein R₄ is heteroarylsubstituted with three R₁₁.

In another embodiment is a compound of Formula IA wherein L₁ is a bondand R₁ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. In another embodimentis a compound of Formula IA wherein L₁ is a bond and R₁ is C₁-C₆alkyl.In another embodiment is a compound of Formula IA wherein L₁ is a bondand R₁ is C₂-C₆alkenyl. In another embodiment is a compound of FormulaIA wherein L₁ is a bond and R₁ is C₁-C₆haloalkyl. In another embodimentis a compound of Formula IA wherein L₁ is a bond and R₁ isC₂-C₉heterocycloalkyl. In another embodiment is a compound of Formula IAwherein L₁ is a bond and R₁ is —C(═O)R₈. In another embodiment is acompound of Formula IA wherein L₁ is a bond, R₁ is —C(═O)R₈, and R₈ isC₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl. In another embodiment is a compound of Formula IA wherein L₁is a bond and R₁ is —C(═O)N(R₉)₂.

In another embodiment is a compound of Formula IA wherein L₁ isC₁-C₆alkyl and R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆haloalkyl, C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. Inanother embodiment is a compound of Formula IA wherein v. In anotherembodiment is a compound of Formula IA wherein L₁ is C₁-C₆alkyl and R₁is —OH. In another embodiment is a compound of Formula IA wherein L₁ isC₁-C₆alkyl and R₁ is —N(R₉)₂. In another embodiment is a compound ofFormula IA wherein L₁ is C₁-C₆alkyl and R₁ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula IA wherein L₁ is C₁-C₆alkyl and R₁is C₂-C₆alkenyl. In another embodiment is a compound of Formula IAwherein L₁ is C₁-C₆alkyl and R₁ is C₁-C₆haloalkyl. In another embodimentis a compound of Formula IA wherein L₁ is C₁-C₆alkyl and R₁ isC₂-C₉heterocycloalkyl. In another embodiment is a compound of Formula IAwherein L₁ is C₁-C₆alkyl and R₁ is —C(═O)R₈. In another embodiment is acompound of Formula IA wherein L₁ is C₁-C₆alkyl, R₁ is —C(═O)R₈, and R₈is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl. In another embodiment is a compound of Formula IA wherein L₁is C₁-C₆alkyl and R₁ is —C(═O)N(R₉)₂.

In some embodiments is a compound of Formula IA wherein R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula IA wherein R₂is C₂-C₆alkenyl. In another embodiment is a compound of Formula IAwherein R₂ is C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula IA wherein R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl.

In another embodiment is a compound of Formula IA wherein L₁ is a bond,R₁ is C₁-C₆alkyl, and R₂ is C₁-C₆alkyl. In another embodiment is acompound of Formula IA wherein L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂ isC₂-C₆alkenyl. In another embodiment is a compound of Formula IA whereinL₁ is a bond, R₁ is C₁-C₆alkyl, and R₂ is C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula IA wherein L₁ is a bond, R₁ isC₁-C₆alkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodimentis a compound of Formula IA wherein L₁ is a bond, R₁ is C₂-C₆alkenyl,and R₂ is C₁-C₆alkyl. In another embodiment is a compound of Formula IAwherein L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula IA wherein L₁ is a bond, R₁is C₂-C₆alkenyl, and R₂ is C₃-C₈cycloalkyl. In another embodiment is acompound of Formula IA wherein L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula IA wherein L₁ is a bond, R₁ is C₁-C₆haloalkyl, and R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula IA wherein L₁is a bond, R₁ is C₁-C₆haloalkyl, and R₂ is C₂-C₆alkenyl. In anotherembodiment is a compound of Formula IA wherein L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodiment is acompound of Formula IA wherein L₁ is a bond, R₁ is C₁-C₆haloalkyl, andR₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compoundof Formula IA wherein L₁ is a bond, R₁ is C₂-C₉heterocycloalkyl, and R₂is C₁-C₆alkyl. In another embodiment is a compound of Formula IA whereinL₁ is a bond, R₁ is C₂-C₉heterocycloalkyl, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula IA wherein L₁ is a bond, R₁is C₂-C₉heterocycloalkyl, and R₂ is C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula IA wherein L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula IA wherein L₁ is a C₁-C₆alkyl, R₁ is—OR₉, R₉ is hydrogen, and R₂ is C₁-C₆alkyl. In another embodiment is acompound of Formula IA wherein L₁ is a C₁-C₆alkyl, R₁ is —OR₉, R₉ ishydrogen, and R₂ is C₂-C₆alkenyl. In another embodiment is a compound ofFormula IA wherein L₁ is a C₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, andR₂ is C₃-C₈cycloalkyl. In another embodiment is a compound of Formula IAwherein L₁ is a C₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with one R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with one R₁₁, R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl.In yet a further embodiment of the aforementioned embodiments is acompound of Formula IA wherein R₄ is phenyl substituted with one R₁₁,R₁₁ is —SO₂R₁₀ and R₁₀ is CH₃. In a further embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with two R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂R₁₀ and one R₁₁ isoptionally substituted C₁-C₆alkyl. In yet a further embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂CH₃ and one R₁₁ is—CH₂OH.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of the aforementioned embodiments isa compound of Formula IA wherein R₃ is hydrogen. In some embodiments ofthe aforementioned embodiments is a compound of Formula IA wherein R₃ ishalogen. In some embodiments of the aforementioned embodiments is acompound of Formula IA wherein R₃ is C₁-C₆alkyl. In some embodiments ofthe aforementioned embodiments is a compound of Formula IA wherein R₃ isC₁-C₆haloalkyl.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein L₁ is a bond. In another embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₁ isC₁-C₆alkyl. In another embodiment of the aforementioned embodiments is acompound of Formula IA wherein R₁ is C₂-C₆alkenyl. In another embodimentof the aforementioned embodiments is a compound of Formula IA wherein R₁is C₁-C₆haloalkyl. In another embodiment of the aforementionedembodiments is a compound of Formula IA wherein R₁ is —CF₃. In anotherembodiment of the aforementioned embodiments is a compound of Formula IAwherein R₁ is C(═O)N(R₉)₂. In another embodiment of the aforementionedembodiments is a compound of Formula IA wherein L₁ is C₁-C₆alkyl; and R₁is —OH.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein -L₁-R₁ is —C(═CH₂)CH₃, isopropyl, —C(═O)NHCH₂CF₃,—CF₃, or —C(CH₃)₂OH. In another embodiment of the aforementionedembodiments is a compound of Formula IA wherein R₂ is C₁-C₆alkyl. Inanother embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₂ is isobutyl. In another embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₂ issec-butyl. In another embodiment of the aforementioned embodiments is acompound of Formula IA wherein R₂ is C₃-C₈cycloalkyl. In anotherembodiment of the aforementioned embodiments is a compound of Formula IAwherein R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₂ isisobutyl, sec-butyl, cyclohexyl, —CH₂-cyclohexyl, or —CH₂-cyclopropyl.In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₃ is hydrogen.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein “optionally substituted” means optionally substitutedby 1, 2, 3, or 4 substituents independently selected from halo, cyano,C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, C₁-C₄ alkylamino, and di(C₁-C₄ alkyl)amino. Inanother embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₄ is phenyl, which is substituted with at least oneR₁₁. In another embodiment of the aforementioned embodiments is acompound of Formula IA wherein at least one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, or —SO₂N(R₁₀)₂. In another embodiment of the aforementionedembodiments is a compound of Formula IA wherein at least one R₁₁ is—SO₂R₁₀. In another embodiment of the aforementioned embodiments is acompound of Formula IA wherein each R₁₀ is independently C₁-C₆alkyl. Inanother embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₄ is phenyl substituted with one R₁₁, wherein R₁₁ is—SO₂R₁₀ and R₁₀ is C₁-C₆alkyl; or R₄ is phenyl substituted with two R₁₁,and one R₁₁ is —SO₂R₁₀ and one R₁₁ is optionally substituted C₁-C₆alkyl.In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein R₄ is phenyl substituted with two R₁₁, wherein oneR₁₁ is —SO₂CH₃ and one R₁₁ is —CH₂OH. In another embodiment of theaforementioned embodiments is a compound of Formula IA wherein R₄ isphenyl substituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ isC₁-C₆alkyl. In another embodiment of the aforementioned embodiments is acompound of Formula IA, wherein n is 0.

In another embodiment of the aforementioned embodiments, the compound isa compound of Formula (IB):

wherein:

R_(11a) is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂; and

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the aforementioned embodiments, the compound isa compound of Formula (IC):

-   -   wherein m is 0 or 1;        or a pharmaceutically acceptable salt thereof.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein:

L₁ is a bond or C₁-C₆alkyl;

R₁ is —OR₉, —C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₃-C₈cycloalkyl, or —C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen;

R₄ is phenyl substituted with at least one R₁₁;

each R₁₁ is independently —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, orC₁-C₆alkyl, wherein said C₁-C₆alkyl is optionally substituted by 1hydroxy;

provided that at least one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or—SO₂N(R₁₀)₂,

each R₁₀ is independently C₁-C₆ alkyl; and

each R₉ is independently hydrogen or C₁-C₆haloalkyl; and

n is 0;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein:

L₁ is a bond or C₁-C₆alkyl;

R₁ is —OR₉, —C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₃-C₈cycloalkyl, or —C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen;

R₄ is phenyl substituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ isC₁-C₆alkyl; or

R₄ is phenyl substituted with two R₁₁, wherein one R₁₁ is —SO₂R₁₀ andone R₁₁ is optionally substituted C₁-C₆alkyl;

each R₉ is independently hydrogen or C₁-C₆haloalkyl; and

n is 0;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the aforementioned embodiments is a compound ofFormula IA wherein:

-L₁-R₁ is —C(═CH₂)CH₃, isopropyl, —C(═O)NHCH₂CF₃, CF₃, or —C(CH₃)₂OH;

R₂ is isobutyl, sec-butyl, cyclohexyl, —CH₂-cyclohexyl, or—CH₂-cyclopropyl;

R₃ is hydrogen;

R₄ is phenyl substituted with two R₁₁, wherein one R₁₁ is —SO₂CH₃ andone R₁₁ is —CH₂OH; or R₄ is phenyl substituted with one R₁₁, wherein R₁₁is —SO₂R₁₀ and R₁₀ is CH₃; and

n is 0;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect is a compound of Formula (II):

wherein:

X is —O—, —S—, or —C(R₆)═C(R₆)—;

L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂;

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl;

R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

R₄ is aryl or heteroaryl; wherein aryl or heteroaryl is substituted withat least one R₁₁;

each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;

each R₆ is independently hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl

R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl,or heteroaryl;

each R₉ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₀ is independently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl;

each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-2;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In some embodiments is a compound of Formula II wherein X is —O—. In afurther embodiment is a compound of Formula II wherein R₄ is heteroarylsubstituted with at least one R₁₁. In some embodiments is a compound ofFormula II wherein R₄ is aryl substituted with at least one R₁₁. In afurther embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl. In a further embodiment is a compound of FormulaII wherein R₄ is phenyl substituted with at least one R₁₁ and each R₁₁is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN, —C(═O)R₁₀,—C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆heteroalkyl, or optionally substituted —C₁-C₆alkyl-aryl. In afurther embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁ and each R₁₁ is independently halogen,—C(═O)R₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, or optionally substituted C₁-C₆alkyl. In a furtherembodiment is a compound of Formula II wherein R₄ is phenyl substitutedwith at least one R₁₁ and each R₁₁ is independently halogen, —SO₂R₁₀, oroptionally substituted C₁-C₆alkyl. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently —SO₂R₁₀ or optionally substituted C₁-C₆alkyl.In a further embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ oroptionally substituted C₁-C₆alkyl, and R₁₁ is C₁-C₆alkyl. In a furtherembodiment is a compound of Formula II wherein R₄ is phenyl substitutedwith at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ or optionallysubstituted C₁-C₆alkyl, and R₁₁ is CH₃. In some embodiments is acompound of Formula II wherein R₄ is aryl substituted with one R₁₁. Insome embodiments is a compound of Formula II wherein R₄ is arylsubstituted with two R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is aryl substituted with three R₁₁. In further embodimentsis a compound of Formula II wherein R₄ is phenyl substituted with oneR₁₁. In further embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁. In further embodiments is a compound ofFormula II wherein R₄ is phenyl substituted with three R₁₁. In someembodiments is a compound of Formula II wherein R₄ is heteroarylsubstituted with one R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is heteroaryl substituted with two R₁₁. In someembodiments is a compound of Formula II wherein R₄ is heteroarylsubstituted with three R₁₁.

In another embodiment is a compound of Formula II wherein X is —O—, L₁is a bond and R₁ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. In another embodimentis a compound of Formula II wherein X is —O—, L₁ is a bond and R₁ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein Xis —O—, L₁ is a bond and R₁ is C₂-C₆alkenyl. In another embodiment is acompound of Formula II wherein X is —O—, L₁ is a bond and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —O—, L₁ is a bond and R₁ is C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ is abond and R₁ is —C(═O)R₈. In another embodiment is a compound of FormulaII wherein X is —O—, L₁ is a bond, R₁ is —C(═O)R₈, and R₈ is C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ is abond and R₁ is —C(═O)N(R₉)₂.

In another embodiment is a compound of Formula II wherein X is —O—, L₁is C₁-C₆alkyl and R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆haloalkyl, C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ isC₁-C₆alkyl and R₁ is —OR₉. In another embodiment is a compound ofFormula II wherein X is —O—, L₁ is C₁-C₆alkyl and R₁ is —OH. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ isC₁-C₆alkyl and R₁ is —N(R₉)₂. In another embodiment is a compound ofFormula II wherein X is —O—, L₁ is C₁-C₆alkyl and R₁ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ isC₁-C₆alkyl and R₁ is C₂-C₆alkenyl. In another embodiment is a compoundof Formula II wherein X is —O—, L₁ is C₁-C₆alkyl and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —O—, L₁ is C₁-C₆alkyl and R₁ is C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ isC₁-C₆alkyl and R₁ is —C(═O)R₈. In another embodiment is a compound ofFormula II wherein X is —O—, L₁ is C₁-C₆alkyl, R₁ is —C(═O)R₈, and R₈ isC₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl. In another embodiment is a compound of Formula II wherein Xis —O—, L₁ is C₁-C₆alkyl and R₁ is —C(═O)N(R₉)₂.

In some embodiments is a compound of Formula II wherein R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein R₂is C₂-C₆alkenyl. In another embodiment is a compound of Formula IIwherein R₂ is C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl.

In another embodiment is a compound of Formula II wherein X is —O—, L₁is a bond, R₁ is C₁-C₆alkyl, and R₂ is C₁-C₆alkyl. In another embodimentis a compound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₁-C₆alkyl, and R₂ is C₂-C₆alkenyl. In another embodiment is a compoundof Formula II wherein X is —O—, L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂is C₃-C₈cycloalkyl. In another embodiment is a compound of Formula IIwherein X is —O—, L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein X is —O—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein Xis —O—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ is abond, R₁ is C₂-C₆alkenyl, and R₂ is C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ is a bond,R₁ is C₂-C₆alkenyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ is a bond,R₁ is C₁-C₆haloalkyl, and R₂ is C₁-C₆alkyl. In another embodiment is acompound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is C₂-C₆alkenyl. In another embodiment is acompound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodiment is acompound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ is a bond,R₁ is C₂-C₉heterocycloalkyl, and R₂ is C₁-C₆alkyl. In another embodimentis a compound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₂-C₆alkenyl. In another embodiment isa compound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodimentis a compound of Formula II wherein X is —O—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula II wherein X is —O—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —O—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁, R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl.In yet a further embodiment of the aforementioned embodiments is acompound of Formula II wherein R₄ is phenyl substituted with one R₁₁,R₁₁ is —SO₂R₁₀ and R₁₀ is CH₃. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂R₁₀ and one R₁₁ isoptionally substituted C₁-C₆alkyl. In yet a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂CH₃ and one R₁₁ is—CH₂OH.

In another embodiment of the aforementioned embodiments is a compound ofFormula II wherein R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of the aforementioned embodiments isa compound of Formula II wherein R₃ is hydrogen. In some embodiments ofthe aforementioned embodiments is a compound of Formula I wherein R₃ ishalogen. In some embodiments of the aforementioned embodiments is acompound of Formula II wherein R₃ is C₁-C₆alkyl. In some embodiments ofthe aforementioned embodiments is a compound of Formula II wherein R₃ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula II wherein X is —S—. In afurther embodiment is a compound of Formula II wherein R₄ is heteroarylsubstituted with at least one R₁₁. In some embodiments is a compound ofFormula II wherein R₄ is aryl substituted with at least one R₁₁. In afurther embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl, optionallysubstituted —C₁-C₆alkyl-aryl, optionally substituted aryl, or optionallysubstituted heteroaryl. In a further embodiment is a compound of FormulaII wherein R₄ is phenyl substituted with at least one R₁₁ and each R₁₁is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN, —C(═O)R₁₀,—C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆heteroalkyl, or optionally substituted —C₁-C₆alkyl-aryl. In afurther embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁ and each R₁₁ is independently halogen,—C(═O)R₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀,—SO₂N(R₁₀)₂, or optionally substituted C₁-C₆alkyl. In a furtherembodiment is a compound of Formula II wherein R₄ is phenyl substitutedwith at least one R₁₁ and each R₁₁ is independently halogen, —SO₂R₁₀, oroptionally substituted C₁-C₆alkyl. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently —SO₂R₁₀ or optionally substituted C₁-C₆alkyl.In a further embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ oroptionally substituted C₁-C₆alkyl, and R₁₁ is C₁-C₆alkyl. In a furtherembodiment is a compound of Formula II wherein R₄ is phenyl substitutedwith at least one R₁₁, each R₁₁ is independently —SO₂R₁₀ or optionallysubstituted C₁-C₆alkyl, and R₁₁ is CH₃. In some embodiments is acompound of Formula II wherein R₄ is aryl substituted with one R₁₁. Insome embodiments is a compound of Formula II wherein R₄ is arylsubstituted with two R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is aryl substituted with three R₁₁. In further embodimentsis a compound of Formula II wherein R₄ is phenyl substituted with oneR₁₁. In further embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁. In further embodiments is a compound ofFormula II wherein R₄ is phenyl substituted with three R₁₁. In someembodiments is a compound of Formula II wherein R₄ is heteroarylsubstituted with one R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is heteroaryl substituted with two R₁₁. In someembodiments is a compound of Formula II wherein R₄ is heteroarylsubstituted with three R₁₁.

In another embodiment is a compound of Formula II wherein X is —S—, L₁is a bond and R₁ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. In another embodimentis a compound of Formula II wherein X is —S—, L₁ is a bond and R₁ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein Xis —S—, L₁ is a bond and R₁ is C₂-C₆alkenyl. In another embodiment is acompound of Formula II wherein X is —S—, L₁ is a bond and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —S—, L₁ is a bond and R₁ is C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ is abond and R₁ is —C(═O)R₈. In another embodiment is a compound of FormulaII wherein X is —S—, L₁ is a bond, R₁ is —C(═O)R₈, and R₈ is C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ is abond and R₁ is —C(═O)N(R₉)₂.

In another embodiment is a compound of Formula II wherein X is —S—, L₁is C₁-C₆alkyl and R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆haloalkyl, C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ isC₁-C₆alkyl and R₁ is —OR₉. In another embodiment is a compound ofFormula II wherein X is —S—, L₁ is C₁-C₆alkyl and R₁ is —OH. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ isC₁-C₆alkyl and R₁ is —N(R₉)₂. In another embodiment is a compound ofFormula II wherein X is —S—, L₁ is C₁-C₆alkyl and R₁ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ isC₁-C₆alkyl and R₁ is C₂-C₆alkenyl. In another embodiment is a compoundof Formula II wherein X is —S—, L₁ is C₁-C₆alkyl and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —S—, L₁ is C₁-C₆alkyl and R₁ is C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ isC₁-C₆alkyl and R₁ is —C(═O)R₈. In another embodiment is a compound ofFormula II wherein X is —S—, L₁ is C₁-C₆alkyl, R₁ is —C(═O)R₈, and R₈ isC₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl. In another embodiment is a compound of Formula II wherein Xis —S—, L₁ is C₁-C₆alkyl and R₁ is —C(═O)N(R₉)₂.

In some embodiments is a compound of Formula II wherein R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein R₂is C₁-C₆alkyl. In another embodiment is a compound of Formula II whereinR₂ is C₂-C₆alkenyl. In another embodiment is a compound of Formula IIwherein R₂ is C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl.

In another embodiment is a compound of Formula II wherein X is —S—, L₁is a bond, R₁ is C₁-C₆alkyl, and R₂ is C₁-C₆alkyl. In another embodimentis a compound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₁-C₆alkyl, and R₂ is C₂-C₆alkenyl. In another embodiment is a compoundof Formula II wherein X is —S—, L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂is C₃-C₈cycloalkyl. In another embodiment is a compound of Formula IIwherein X is —S—, L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein X is —S—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein Xis —S—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ is abond, R₁ is C₂-C₆alkenyl, and R₂ is C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ is a bond,R₁ is C₂-C₆alkenyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ is a bond,R₁ is C₁-C₆haloalkyl, and R₂ is C₁-C₆alkyl. In another embodiment is acompound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is C₂-C₆alkenyl. In another embodiment is acompound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodiment is acompound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₁-C₆haloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ is a bond,R₁ is C₂-C₉heterocycloalkyl, and R₂ is C₁-C₆alkyl. In another embodimentis a compound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₂-C₆alkenyl. In another embodiment isa compound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodimentis a compound of Formula II wherein X is —S—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula II wherein X is —S—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —S—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁, R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl.In yet a further embodiment of the aforementioned embodiments is acompound of Formula II wherein R₄ is phenyl substituted with one R₁₁,R₁₁ is —SO₂R₁₀ and R₁₀ is CH₃. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂R₁₀ and one R₁₁ isoptionally substituted C₁-C₆alkyl. In yet a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂CH₃ and one R₁₁ is—CH₂OH.

In another embodiment of the aforementioned embodiments is a compound ofFormula II wherein R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of the aforementioned embodiments isa compound of Formula II wherein R₃ is hydrogen. In some embodiments ofthe aforementioned embodiments is a compound of Formula I wherein R₃ ishalogen. In some embodiments of the aforementioned embodiments is acompound of Formula II wherein R₃ is C₁-C₆alkyl. In some embodiments ofthe aforementioned embodiments is a compound of Formula II wherein R₃ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula II wherein X is —CH═CH—. Ina further embodiment is a compound of Formula II wherein R₄ isheteroaryl substituted with at least one R₁₁. In some embodiments is acompound of Formula II wherein R₄ is aryl substituted with at least oneR₁₁. In a further embodiment is a compound of Formula II wherein R₄ isphenyl substituted with at least one R₁₁. In a further embodiment is acompound of Formula II wherein R₄ is phenyl substituted with at leastone R₁₁ and each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂,—CN, —C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀,—SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl,optionally substituted —C₁-C₆alkyl-aryl, optionally substituted aryl, oroptionally substituted heteroaryl. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁ andeach R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂, —CN,—C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀, —SOR₁₀,—SO₂R₁₀, —SO₂N(R₁₀)₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆heteroalkyl, or optionally substituted—C₁-C₆alkyl-aryl. In a further embodiment is a compound of Formula IIwherein R₄ is phenyl substituted with at least one R₁₁ and each R₁₁ isindependently halogen, —C(═O)R₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀,NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, or optionally substitutedC₁-C₆alkyl. In a further embodiment is a compound of Formula II whereinR₄ is phenyl substituted with at least one R₁₁ and each R₁₁ isindependently halogen, —SO₂R₁₀, or optionally substituted C₁-C₆alkyl. Ina further embodiment is a compound of Formula II wherein R₄ is phenylsubstituted with at least one R₁₁ and each R₁₁ is independently —SO₂R₁₀or optionally substituted C₁-C₆alkyl. In a further embodiment is acompound of Formula II wherein R₄ is phenyl substituted with at leastone R₁₁, each R₁₁ is independently —SO₂R₁₀ or optionally substitutedC₁-C₆alkyl, and R₁₁ is C₁-C₆alkyl. In a further embodiment is a compoundof Formula II wherein R₄ is phenyl substituted with at least one R₁₁,each R₁₁ is independently —SO₂R₁₀ or optionally substituted C₁-C₆alkyl,and R₁₁ is CH₃. In some embodiments is a compound of Formula II whereinR₄ is aryl substituted with one R₁₁. In some embodiments is a compoundof Formula II wherein R₄ is aryl substituted with two R₁₁. In someembodiments is a compound of Formula II wherein R₄ is aryl substitutedwith three R₁₁. In further embodiments is a compound of Formula IIwherein R₄ is phenyl substituted with one R₁₁. In further embodiments isa compound of Formula II wherein R₄ is phenyl substituted with two R₁₁.In further embodiments is a compound of Formula II wherein R₄ is phenylsubstituted with three R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is heteroaryl substituted with one R₁₁. In someembodiments is a compound of Formula II wherein R₄ is heteroarylsubstituted with two R₁₁. In some embodiments is a compound of FormulaII wherein R₄ is heteroaryl substituted with three R₁₁.

In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is a bond and R₁ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. In another embodimentis a compound of Formula II wherein X is —CH═CH—, L₁ is a bond and R₁ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein Xis —CH═CH—, L₁ is a bond and R₁ is C₂-C₆alkenyl. In another embodimentis a compound of Formula II wherein X is —CH═CH—, L₁ is a bond and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is a bond and R₁ is C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—, L₁is a bond and R₁ is —C(═O)R₈. In another embodiment is a compound ofFormula II wherein X is —CH═CH—, L₁ is a bond, R₁ is —C(═O)R₈, and R₈ isC₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl. In another embodiment is a compound of Formula II wherein Xis —CH═CH—, L₁ is a bond and R₁ is —C(═O)N(R₉)₂.

In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is C₁-C₆alkyl and R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆haloalkyl, C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—, L₁is C₁-C₆alkyl and R₁ is —OR₉. In another embodiment is a compound ofFormula II wherein X is —CH═CH—, L₁ is C₁-C₆alkyl and R₁ is —OH. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—, L₁is C₁-C₆alkyl and R₁ is —N(R₉)₂. In another embodiment is a compound ofFormula II wherein X is —CH═CH—, L₁ is C₁-C₆alkyl and R₁ is C₁-C₆alkyl.In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is C₁-C₆alkyl and R₁ is C₂-C₆alkenyl. In another embodiment is acompound of Formula II wherein X is —CH═CH—, L₁ is C₁-C₆alkyl and R₁ isC₁-C₆haloalkyl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is C₁-C₆alkyl and R₁ is C₂-C₉heterocycloalkyl.In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is C₁-C₆alkyl and R₁ is —C(═O)R₈. In another embodiment is a compoundof Formula II wherein X is —CH═CH—, L₁ is C₁-C₆alkyl, R₁ is —C(═O)R₈,and R₈ is C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl,aryl, or heteroaryl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is C₁-C₆alkyl and R₁ is —C(═O)N(R₉)₂.

In some embodiments is a compound of Formula II wherein R₂ isC₁-C₆alkyl. In another embodiment is a compound of Formula II wherein R₂is C₁-C₆alkyl. In another embodiment is a compound of Formula II whereinR₂ is C₂-C₆alkenyl. In another embodiment is a compound of Formula IIwherein R₂ is C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl.

In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is a bond, R₁ is C₁-C₆alkyl, and R₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula II wherein X is —CH═CH—, L₁ is abond, R₁ is C₁-C₆alkyl, and R₂ is C₂-C₆alkenyl. In another embodiment isa compound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₁-C₆alkyl, and R₂ is C₃-C₈cycloalkyl. In another embodiment is acompound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₁-C₆alkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodimentis a compound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₂-C₆alkenyl, and R₂ is C₁-C₆alkyl. In another embodiment is a compoundof Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ is C₂-C₆alkenyl,and R₂ is C₂-C₆alkenyl. In another embodiment is a compound of FormulaII wherein X is —CH═CH—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ isC₃-C₈cycloalkyl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is a bond, R₁ is C₂-C₆alkenyl, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein X is —CH═CH—, L₁ is a bond, R₁ is C₁-C₆haloalkyl, andR₂ is C₁-C₆alkyl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is a bond, R₁ is C₁-C₆haloalkyl, and R₂ isC₂-C₆alkenyl. In another embodiment is a compound of Formula II whereinX is —CH═CH—, L₁ is a bond, R₁ is C₁-C₆haloalkyl, and R₂ isC₃-C₈cycloalkyl. In another embodiment is a compound of Formula IIwherein X is —CH═CH—, L₁ is a bond, R₁ is C₁-C₆haloalkyl, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In another embodiment is a compound ofFormula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₁-C₆alkyl. In another embodiment is acompound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₂-C₆alkenyl. In another embodiment isa compound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is C₃-C₈cycloalkyl. In another embodimentis a compound of Formula II wherein X is —CH═CH—, L₁ is a bond, R₁ isC₂-C₉heterocycloalkyl, and R₂ is —C₁-C₆alkyl-C₃-C₈cycloalkyl. In anotherembodiment is a compound of Formula II wherein X is —CH═CH—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula II wherein X is —CH═CH—, L₁ is aC₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₂-C₆alkenyl. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—, L₂is a C₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is C₃-C₈cycloalkyl.In another embodiment is a compound of Formula II wherein X is —CH═CH—,L₁ is a C₁-C₆alkyl, R₁ is —OR₉, R₉ is hydrogen, and R₂ is—C₁-C₆alkyl-C₃-C₈cycloalkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with one R₁₁, R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl.In yet a further embodiment of the aforementioned embodiments is acompound of Formula II wherein R₄ is phenyl substituted with one R₁₁,R₁₁ is —SO₂R₁₀ and R₁₀ is CH₃. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁. In a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂R₁₀ and one R₁₁ isoptionally substituted C₁-C₆alkyl. In yet a further embodiment of theaforementioned embodiments is a compound of Formula II wherein R₄ isphenyl substituted with two R₁₁, and one R₁₁ is —SO₂CH₃ and one R₁₁ is—CH₂OH.

In another embodiment of the aforementioned embodiments is a compound ofFormula II wherein R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of the aforementioned embodiments isa compound of Formula II wherein R₃ is hydrogen. In some embodiments ofthe aforementioned embodiments is a compound of Formula II wherein R₃ ishalogen. In some embodiments of the aforementioned embodiments is acompound of Formula II wherein R₃ is C₁-C₆alkyl. In some embodiments ofthe aforementioned embodiments is a compound of Formula II wherein R₃ isC₁-C₆haloalkyl.

In another embodiment is a compound of Formula II wherein X is —CH═CH—;and -L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, or C₁-C₆haloalkyl. In anotherembodiment is a compound of Formula II wherein X is —CH═CH—; and -L₁-R₁is —CF₃ or —C(CH₃)₂OH. In another embodiment is a compound of Formula IIwherein X is —CH═CH—; and R₂ is C₁-C₆ alkyl. In another embodiment is acompound of Formula II wherein X is —CH═CH—; and R₂ is isobutyl. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—; andR₃ is hydrogen. In another embodiment is a compound of Formula IIwherein X is —CH═CH—; and R₄ is phenyl; wherein said phenyl issubstituted with at least one R₁₁. In another embodiment is a compoundof Formula II wherein X is —CH═CH—; and at least one R₁₁ is —NR₁₀SO₂R₁₀,—SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂. In another embodiment is a compound ofFormula II wherein X is —CH═CH—; and at least one R₁₁ is —SO₂R₁₀. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—; andeach R₁₀ is independently C₁-C₆ alkyl. In another embodiment is acompound of Formula II wherein X is —CH═CH—; and each R₁₀ is methyl. Inanother embodiment is a compound of Formula II wherein X is —CH═CH—; andR₄ is phenyl substituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ isC₁-C₆alkyl; or R₄ is phenyl substituted with two R₁₁, and one R₁₁ is—SO₂R₁₀ and one R₁₁ is optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula II wherein X is —CH═CH—; and R₄ isphenyl substituted with two R₁₁, wherein one R₁₁ is —SO₂CH₃ and one R₁₁is —CH₂OH. In another embodiment is a compound of Formula II wherein Xis —CH═CH—; and R₄ is phenyl substituted with one R₁₁, wherein R₁₁ is—SO₂R₁₀ and R₁₀ is C₁-C₆alkyl. In another embodiment is a compound ofFormula II wherein X is —CH═CH—; and “optionally substituted” meansoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo, cyano, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, C₁-C₄ alkylamino, anddi(C₁-C₄ alkyl)amino.

In another embodiment is a compound of Formula II wherein X is —CH═CH,the compound is a compound of Formula (IIA):

wherein:

R_(11a) is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂; and

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula II wherein X is —CH═CH—,wherein the compound is a compound of Formula (IIB):

wherein m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula II wherein:

X is —CH═CH—;

-L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, or C₁-C₆haloalkyl;

R₂ is C₁-C₆ alkyl;

R₃ is hydrogen;

R₄ is phenyl; wherein said phenyl is substituted with at least one R₁₁;

each R₁₁ is independently —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, orC₁-C₆alkyl, wherein said C₁-C₆alkyl is optionally substituted by 1hydroxy;

provided that at least one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or—SO₂N(R₁₀)₂,

each R₁₀ is independently C₁-C₆ alkyl; and

n is 0.

In another embodiment is a compound of Formula II wherein:

X is —CH═CH—;

-L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, or C₁-C₆haloalkyl;

R₂ is C₁-C₆ alkyl;

R₃ is hydrogen;

R₄ is phenyl; wherein said phenyl is substituted with at least one R₁₁;wherein each R₁₁ is independently —SO₂R₁₀, or C₁-C₆alkyl, wherein saidC₁-C₆alkyl is optionally substituted by 1 hydroxy; provided that atleast one R₁₁ is —SO₂R₁₀,

each R₁₀ is independently C₁-C₆ alkyl; and

n is 0.

In another embodiment, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In some embodiments, the therapeutic agent(s) (e.g. compound of FormulaI, IA, II or III is present in the pharmaceutical composition as apharmaceutically acceptable salt. In some embodiments, any compounddescribed above is suitable for any method or composition describedherein.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns. In some embodiments, acompound of Formula I, IA, IB, IC, II, IIA, or IIB is used as a singleenantiomer. In some embodiments, a compound of Formula I, IA, IB, IC,II, IIA, or IIB is used as a racemic mixture.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structurespresented herein, as well as active metabolites of these compoundshaving the same type of activity. In some situations, compounds mayexist as tautomers. All tautomers are included within the scope of thecompounds presented herein. In specific embodiments, the compounds orsalts described herein exist in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. In otherembodiments, the compounds or salts described herein exist in unsolvatedform.

In some embodiments, the compounds of Formula I, IA, IB, IC, II, IIA, orIIB or salts thereof described herein include solvent addition forms orcrystal forms thereof, particularly solvates or polymorphs. Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and may be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol.

In some embodiments, sites on the compounds of Formula I, IA, IB, IC,II, IIA, or IIB disclosed herein are susceptible to various metabolicreactions. Therefore incorporation of appropriate substituents at theplaces of metabolic reactions will reduce, minimize or eliminate themetabolic pathways. In specific embodiments, the appropriate substituentto decrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium oran alkyl group.

In some embodiments, the compounds of Formula I, IA, IB, IC, II, IIA, orIIB disclosed herein are isotopically-labeled, which are identical tothose recited in the various formulae and structures presented herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. In some embodiments, one or morehydrogen atoms are replaced with deuterium. In some embodiments,metabolic sites on the compounds described herein are deuterated. Insome embodiments, substitution with deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, compounds described herein, such as compounds ofFormula I, IA, IB, IC, II, IIA, or IIB, are in various forms, includingbut not limited to, amorphous forms, milled forms and nano-particulateforms. In addition, compounds described herein include crystallineforms, also known as polymorphs. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,melting points, density, hardness, crystal shape, optical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTTR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles and/or nucleophiles to form new functional groups orsubstituents. Table IA entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected non-limiting examples of covalentlinkages and precursor functional groups which yield the covalentlinkages. Table IA may be used as guidance toward the variety ofelectrophiles and nucleophiles combinations available that providecovalent linkages. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

TABLE IA Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Alkyl amines alkylhalides amines/anilines Esters alkyl halides carboxylic acids Thioethersalkyl halides Thiols Ethers alkyl halides alcohols/phenols Thioethersalkyl sulfonates Thiols Esters Anhydrides alcohols/phenols CarboxamidesAnhydrides amines/anilines Thiophenols aryl halides Thiols Aryl aminesaryl halides Amines Thioethers Azindines Thiols Carboxamides carboxylicacids amines/anilines Esters carboxylic acids Alcohols hydrazinesHydrazides carboxylic acids N-acylureas or Anhydrides carbodiimidescarboxylic acids Esters diazoalkanes carboxylic acids ThioethersEpoxides Thiols Thioethers haloacetamides Thiols Ureas Isocyanatesamines/anilines Urethanes Isocyanates alcohols/phenols Thioureasisothiocyanates amines/anilines Thioethers Mal eimides Thiols Alkylamines sulfonate esters amines/anilines hioethers sulfonate estersThiols Sulfonamides sulfonyl halides amines/anilines Sulfonate esterssulfonyl halides phenol s/alcohols

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic. In some embodiments, “alkyl” is abranched or straight-chain alkyl.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which two atoms ofthe alkyl group form a double bond that is not part of an aromaticgroup. Non-limiting examples of an alkenyl group include —CH═CH₂,—C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and —C(CH₃)═CHCH₃. The alkenylmoiety may be branched, straight chain, or cyclic (in which case, itwould also be known as a “cycloalkenyl” group). Alkenyl groups may have2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted.Depending on the structure, an alkenyl group can be a monoradical or adiradical (i.e., an alkenylene group). In some embodiments, “alkenyl” isa branched or straight-chain alkenyl.

The term “alkynyl” refers to a type of alkyl group in which the twoatoms of the alkyl group form a triple bond. Non-limiting examples of analkynyl group include —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The“R” portion of the alkynyl moiety may be branched, straight chain, orcyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can besubstituted or unsubstituted. Depending on the structure, an alkynylgroup can be a monoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂Cl, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. In some embodiments, “optionally substituted” meansoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo, cyano, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, C₁-C₄ alkylamino, anddi(C₁-C₄ alkyl)amino. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, above.

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formulas I, IA, orII, as well as active metabolites of these compounds having the sametype of activity. In some situations, compounds may exist as tautomers.All tautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Methods of Treatment and Prevention

In one embodiment, provided herein are methods for stimulation of LXRactivity in a cell by contacting the cell with an LXR modulator.Examples of such LXR modulators are described above. Other LXRmodulators that can be used to stimulate the LXR activity are identifiedusing screening assays that select for such compounds, as described indetail herein.

In another aspect, provided herein are methods of modulating LXRactivity for the treatment of diseases, disorders or conditionsdescribed herein. Accordingly, in an exemplary embodiment, providedherein are methods which involve contacting a cell with an LXR modulatorthat induces TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT,ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, and/or decorinexpression and/or inhibits TNFα, MMP1, MMP3, and/or IL-8 expression.These methods are performed in vitro (e.g., by culturing the cell withan LXR modulator) or, alternatively, in vivo (e.g., by administering anLXR modulator to a subject). As such, the present methods are directedto treating a subject that would benefit from induction of TIMP1, ASAH1,SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, and/or decorin expression and/or inhibitionof TNFα, MMP1, MMP3, and/or IL-8 expression.

LXR modulators increase expression of genes involved in fatty acidsynthesis and lipid transport. The LXR ligand induced the expression ofgenes involved in fatty acid synthesis, namely SREBF1, SREBF2, FASN, andSCD, and genes involved in cholesterol and phospholipid transport namelyAPOE, APOD, ABCG1, ABCA1, ABCA12, ABCA2, and ABCA13. LXR modulatorsincrease the expression of LASS4 and SMPD2.

Pharmaceutical Compositions and Methods of Administration of LXRModulators

Administration of LXR modulators as described herein can be in anypharmacological form including a therapeutically effective amount of anLXR modulator alone or in combination with a pharmaceutically acceptablecarrier. The term “subject” is intended to include living organisms inwhich an immune response can be elicited, for example, mammals.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula I, IA or II described herein, with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Thecompounds of Formula I, IA or II can be used singly or in combinationwith one or more therapeutic agents as components of mixtures (as incombination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula I, IA or II described herein, can beformulated into any suitable dosage form, including but not limited to,aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries,suspensions, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

For treatment of solid tumors, localized delivery is also an option.Such delivery may be by injection, or may be topical, transmucosal, andthe like. If the drugs are directed to treatment of melanoma, topicaladministration is a viable option.

For systemic parenteral delivery, a variety of physiologicallyacceptable carriers is available, including nanoparticulateformulations, liposomes, micelles, and the like. Such carriers can alsobe targeted using antibodies or fragments thereof specific for thetargets, or by using receptor ligands. “Antibodies” includes all forms,including human and humanized antibodies as well as recombinantlyproduced single-chain antibodies and fragments.

Formulations for systemic administration by parenteral routes mayinclude aqueous as well as lipophilic carriers. Similarly, formulationsfor administration, for example, by inhalation will include carriersthat promote absorption across the nasal barrier and may be administeredby aerosol spray using propellants such as trichlorofluoromethane,carbon dioxide or other propellant. The formulation to be administeredmay also be in the form of a powder or slurry.

The pharmaceutical compositions described herein, which include acompound of Formula I, IA or II described herein, may be administeredusing sustained release formulations including implants. Such implantsmay be used proximal to any solid tumor or implanted within said tumor.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe LXR modulator and the particular therapeutic effect to be achievedand (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the LXR modulatoractivities disclosed herein in assay preparations of target cells. Exactdosages are determined in conjunction with standard dose-responsestudies. It will be understood that the amount of the compositionactually administered will be determined by a practitioner, in the lightof the relevant circumstances including the condition or conditions tobe treated, the choice of composition to be administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such LXR modulators can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. LXR modulators that exhibit large therapeuticindices are preferred. While LXR modulators that exhibit toxic sideeffects may be used, care should be taken to design a delivery systemthat targets such modulators to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch LXR modulators lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any LXR modulatorused in a method described herein, the therapeutically effective dosecan be estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofLXR modulator that achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

Monitoring the influence of LXR modulators on the induction of TIMP1,ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, and/or decorin expression and/or inhibitionof TNFα, MMP1, MMP3, and/or IL-8 expression is applied in clinicaltrials. For example, the effectiveness of an LXR modulator is monitoredin clinical trials of subjects exhibiting increased TIMP1, ASAH1,SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, and/or decorin expression and/or decreasedTNFα, MMP1, MMP3, and/or IL-8 expression. In such clinical trials, theexpression of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR,CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα,MMP1, MMP3, and/or IL-8 is used as a “read out” or marker.

Thus, to study the effect of LXR modulators, for example, in a clinicaltrial, cells are isolated and RNA prepared and analyzed for the levelsof expression of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR,CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα,MMP1, MMP3, and/or IL-8. The levels of gene expression (i.e., a geneexpression pattern) is quantified, for example, by Northern blotanalysis or RT-PCR, by measuring the amount of protein produced, or bymeasuring the levels of activity of TIMP1, ASAH1, SPTLC1, SMPD1, LASS2,TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn,decorin, TNFα, MMP1, MMP3, and/or IL-8, all by methods well known tothose of ordinary skill in the art. In this way, the gene expressionpattern serves as a marker, indicative of the physiological response ofthe cells to the LXR modulator. Accordingly, this response state isdetermined before, and at various points during, treatment of theindividual with the LXR modulator.

Also provided is a method for monitoring the effectiveness of treatmentof a subject with an LXR modulator comprising the steps of (i) obtaininga pre-administration sample from a subject prior to administration ofthe LXR modulator; (ii) detecting the level of expression of TIMP1,ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα, MMP1, MMP3, and/or IL-8;(iii) obtaining one or more post-administration samples from thesubject; (iv) detecting the level of expression of TIMP1, ASAH1, SPTLC1,SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12,ABCA13, ABCG1, αSyn, decorin, TNFα, MMP1, MMP3, and/or IL-8 in thepost-administration samples; (v) comparing the level of expression ofTIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1,ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα, MMP1, MMP3, and/orIL-8 in the pre-administration sample with the TIMP1, ABCA12, decorin,TNFα, MMP1, MMP3, and/or IL-8 expression in the post administrationsample or samples; and (vi) altering the administration of the LXRmodulator to the subject accordingly.

For example, increased administration of the LXR modulator may bedesirable to increase TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3,GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, and/ordecorin expression to higher levels than detected and/or reduce TNFα,MMP1, MMP3, and/or IL-8 expression to lower levels than detected, thatis, to increase the effectiveness of the LXR modulator. Alternatively,decreased administration of the LXR modulator may be desirable todecrease TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT,ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, and/or decorinexpression to lower levels than detected or activity and/or to increaseTNFα, MMP1, MMP3, and/or IL-8 expression to higher levels than detected,that is, to decrease the effectiveness of the LXR modulator. Accordingto such an embodiment, TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3,GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin,TNFα, MMP1, MMP3, and/or IL-8 expression may be used as an indicator ofthe effectiveness of an LXR modulator, even in the absence of anobservable phenotypic response.

Screening Assays

In one embodiment, expression levels of cytokines and metalloproteasesdescribed herein are used to facilitate design and/or identification ofcompounds that work through an LXR-based mechanism. Accordingly providedherein are methods (also referred to herein as “screening assays”) foridentifying modulators, i.e., LXR modulators, that have a stimulatory orinhibitory effect on, for example, TIMP1, ASAH1, SPTLC1, SMPD1, LASS2,TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn,decorin, TNFα, MMP1, MMP3, and/or IL-8 expression.

An exemplary screening assay is a cell-based assay in which a cell thatexpresses LXR is contacted with a test compound, and the ability of thetest compound to modulate TIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1,GPX3, GSR, CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn,decorin, TNFα, MMP1, MMP3, and/or IL-8 expression through an LXR-basedmechanism. Determining the ability of the test compound to modulateTIMP1, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1,ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα, MMP1, MMP3, and/orIL-8 expression is accomplished by monitoring, for example, DNA, mRNA,or protein levels, or by measuring the levels of activity of TIMP1,ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR, CAT, ApoE, ABCA1, ABCA2,ABCA12, ABCA13, ABCG1, αSyn, decorin, TNFα, MMP1, MMP3, and/or IL-8. Thecell, for example, is of mammalian origin, e.g., human.

Novel modulators identified by the above-described screening assays areused for treatments as described herein.

EXAMPLES

The following examples are offered for purposes of illustration, and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Example 1: Synthesis of1-isobutyl-5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazole(4)

Following the reaction sequence above, the title compound 4 was preparedstarting from 1-(4-bromophenyl)ethanone 1 and ethyl trifluoroacetate.LCMS: 423.25.10 (M+1)⁺; HPLC: 96.20% (@ 210 nm-370 nm) (R_(t); 8.064;Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFAin water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30°C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for1.5 min, 9.51-12 min 5% B); ¹H NMR (CDCl₃, 400 MHz) δ 8.22 (s, 1H), 7.95(dd, 2H), 7.74 (d, 2H, J=7.6 Hz), 7.72 (d, 1H), 7.50 (d, 2H, J=7.6 Hz),7.26 (s, 1H), 4.02 (d, 2H), 3.12 (s, 3H), 2.24 (m, 1H), 0.81 (d, 6H).

Example 2: Synthesis of(4′-(1-isobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-(methylsulfonyl)biphenyl-4-yl)methanol(5)

The title compound 5 was prepared starting from5-(4-bromophenyl)-1-isobutyl-3-(trifluoromethyl)-1H-pyrazole 3A and(2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol.LCMS: 453.30.10 (M+1)⁺; HPLC: 96.20% (@ 210 nm-370 nm) (R_(t); 7.649;Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFAin water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30°C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for1.5 min, 9.51-12 min 5% B); ¹H NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 7.92(brd, 1H), 7.74 (d, 2H, J=7.6 Hz), 7.71 (d, 1H), 7.50 (d, 2H, J=7.6 Hz),7.26 (s, 1H), 6.56 (s, 1H), 5.02 (brd, 2H), 4.00 (d, 2H), 3.24 (s, 1H),3.00 (m, 1H), 2.24 (m, 1H), 0.80 (s, 6H).

Example 1A: Alternative Synthesis1-isobutyl-5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazole(4)

Step 1: 1-(4-Bromophenyl)-4,4,4-trifluorobutane-1,3-dione

To a stirred solution of 1-(4-bromophenyl)ethanone (25 g, 125.6 mmol) indry THF (250 mL) at −78° C., LiHMDS (1 M, 188 mL, 188.4 mmol) was addedand the solution was stirred at same temperature for 1 h. To thissolution, ethyl 2,2,2-trifluoroacetate (22.44 mL, 188.4 mmol) in THF (20mL) was added at −78° C. and the resulting reaction mixture was stirredat rt for 12 h. The progress of the reaction was monitored by TLC. Uponcompletion the reaction mixture was quenched with aqueous sat. NH₄Clsolution and extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under reduced pressureresulting in a crude compound which was purified by columnchromatography to afford the title compound (35 g, 94.4%).

Step 2: 5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazole

To a stirred solution of1-(4-Bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1 g, 3.39 mmol) inMeOH (10 mL), hydrazine hydrate (0.186 g, 3.73 mmol) was added, and theresulting reaction mixture was stirred at 90° C. for 6 h. The progressof the reaction was monitored by TLC. Upon completion the reactionmixture was concentrated to dryness under reduced pressure. The residueobtained was diluted with water and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure resulting in a crude compound whichwas purified by column chromatography to afford the title compound (0.6g, 61.2%).

Step 3: 5-(4-Bromophenyl)-1-isobutyl-3-(trifluoromethyl)-1H-pyrazole

To a stirred solution of5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole (1 g, 3.45 mmol) inACN (10 mL), 1-bromo-2-methylpropane (0.709 g, 5.18 mmol) and CS₂CO₃(2.24 g, 6.90 mmol) were added and the resulting reaction mixture wasstirred at 80° C. for 6 h. The progress of the reaction was monitored byTLC. Upon completion the reaction mixture was concentrated to drynessunder reduced pressure. The residue obtained was diluted with water andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure resultingin a crude compound which was purified by column chromatography toafford the title compound (0.44 g, 38%).

Step 4:1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-(trifluoromethyl)-1H-pyrazole(4)

To a stirred solution of5-(4-bromophenyl)-1-isobutyl-3-(trifluoromethyl)-1H-pyrazole (5.3 g,15.32 mmol) and (3-(methylsulfonyl)phenyl)boronic acid (3 g, 15.32 mmol)in dioxane/water mixture (50 mL+10 mL), Na₂CO₃ (3.2 g, 30.64 mmol) wasadded and the solution was purged with argon for 10 min. Then Pd (PPh₃)₄(1.76 g, 1.53 mmol) was added and argon was purged again for 10 min. Thereaction mass was heated at 100° C. for 3 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixturediluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by column chromatography toafford the desired compound 4 (5.2 g, 80.5%). LCMS: 423.10 (M+1)⁺; HPLC:98.55% (@ 210 nm-400 nm) (Rt; 10.354; Method: YMC TRIART C-18 (150mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase: A; 0.05% TFA inwater/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient;Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, CDCl₃) δ8.22 (d, J=2.2 Hz, 1H), 8.01-7.90 (m, 2H), 7.78-7.66 (m, 3H), 7.51 (dd,J=8.3, 2.4 Hz, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.01 (dd, J=7.7, 2.4 Hz,2H), 3.13 (d, J=2.3 Hz, 3H), 2.23 (hept, J=6.8 Hz, 1H), 0.80 (dd, J=7.0,2.4 Hz, 6H).

Example 2A. Alternative Synthesis of(4′-(1-isobutyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)methanol(5)

To a stirred solution of5-(4-bromophenyl)-1-isobutyl-3-(trifluoromethyl)-1H-pyrazole of Example1A, step 4 (5 g, 14.45 mmol) and(2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(6.81 g, 21.68 mmol) in dioxane/water mixture (50 mL+10 mL), Na₂CO₃(3.06 g, 28.90 mmol) was added and the solution was purged with argonfor 10 min. Then Pd (PPh₃)₄ (1.67 g, 1.445 mmol) was added and argon waspurged again for 10 min. The reaction mass was heated at 100° C. for 16h. The progress of the reaction was monitored by TLC. Upon completionthe reaction mixture diluted with water and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography to afford the desired compound 5 (3.1 g, 47.4%).LCMS: 453.10 (M+1)⁺; HPLC: 95.04% (@ 210 nm-400 nm) (Rt; 9.773; Method:YMC TRIART C-18 (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase:A; 0.05% TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col.Temp.: Ambient; Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8min, Hold till 9.5 min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR(400 MHz, CDCl₃) δ 8.32 (d, J=1.9 Hz, 1H), 7.92 (dd, J=7.9, 2.0 Hz, 1H),7.78-7.65 (m, 3H), 7.54-7.44 (m, 2H), 6.57 (s, 1H), 5.02 (d, J=6.7 Hz,2H), 4.01 (d, J=7.5 Hz, 2H), 3.24 (s, 3H), 3.02 (t, J=6.8 Hz, 1H), 2.23(hept, J=7.0 Hz, 1H), 0.80 (d, J=6.7 Hz, 6H).

Example 3: Synthesis of1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide(6)

Step 1: Ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate

To a stirred solution of 1-(4-bromophenyl)ethanone (5 g, 25.38 mmol) indry THF (50 mL) at −78° C., LiHMDS (1 M, 28 mL, 27.91 mmol) was addedand the solution was stirred at same temperature for 1 h. To thissolution, diethyl oxalate (4.08 g, 27.91 mmol) in THF (10 mL) was addedat −78° C. and the resulting reaction mixture was stirred at rt for 12h. The progress of the reaction was monitored by TLC and LCMS. Uponcompletion the reaction mixture was quenched with aqueous sat. NH₄Clsolution and extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under reduced pressureresulting in a crude compound which was purified by columnchromatography to afford the title compound (2.5 g, 33.3%).

Step 2: Ethyl 5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate

To a stirred solution of the product of the previous step (1 g, 3.35mmol) in EtOH (20 mL), isobutyl hydrazine hydrochloride (0.45 g, 3.69mmol) was added and the resulting reaction mixture was stirred at 80° C.for 3 h. The progress of the reaction was monitored by TLC. Uponcompletion the reaction mixture was concentrated to dryness underreduced pressure. The residue obtained was diluted with water andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to afforda crude compound which was purified by column chromatography to affordethyl 5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate (0.7 g,60%) which was confirmed by NOE experiment.

Step 3: Ethyl1-isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate (0.7 g, 2.0 mmol)and (3-(methylsulfonyl)phenyl)boronic acid (0.42 g, 2.10 mmol) indioxane/water mixture (8 mL+2 mL), Na₂CO₃ (0.530 g, 5.0 mmol) was added,and the solution was purged with argon for 10 min. Then Pd (PPh₃)₄(0.231 g, 0.2 mmol) was added and argon was purged again for 10 min. Thereaction mass was heated at 80° C. for 6 h. The progress of the reactionwas monitored by TLC. Upon completion the reaction mixture diluted withwater and extracted with ethyl acetate. The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by column chromatography to afford the desiredcompound (0.5 g, 59%). LCMS: 427.15 (M+1)⁺; HPLC: 99.83% (@ 210 nm-400nm) (Rt; 9.552; Method: YMC TRIARTC-18 (150 mm×4.6 mm×3μ);ID:E-AC-2/13/COL/03, Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA inacetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min, 15% B in13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (d,J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.94 (t, J=7.6 Hz, 3H), 7.78 (t,J=7.8 Hz, 1H), 7.67 (d, J=7.9 Hz, 2H), 6.91 (d, J=1.9 Hz, 1H), 4.30 (q,J=7.0 Hz, 2H), 4.09 (d, J=7.4 Hz, 2H), 3.33 (s, 3H), 2.05 (tq, J=12.4,7.0 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 0.72 (d, J=6.6 Hz, 6H).

Step 4:1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazole-3-carboxylicacid

To a stirred solution of the product of the previous step (0.5 g, 1.17mmol) in THF (5 mL), LiOH (0.056 g, 2.34 mmol in 2 mL H₂O) was added andthe reaction mass was stirred at rt for 12 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixture wasconcentrated to dryness under reduced pressure. The residue obtained wasacidified with 1N HCl up to pH=2 and extracted with 10% MeOH/DCM. Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by acetonitrile anddiethyl ether washings to afford the desired compound (0.35 g, 75%).LCMS: 399.25 (M+1)⁺; HPLC: 98.86% (@ 210 nm-400 nm) (Rt; 7.756; Method:YMC TRIART C-18 (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase:A; 0.05% TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col.Temp.: Ambient; Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8min, Hold till 9.5 min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR(400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.24 (d, J=1.8 Hz, 1H), 8.12 (dt,J=8.0, 1.3 Hz, 1H), 7.94 (dd, J=10.1, 7.7 Hz, 3H), 7.78 (t, J=7.8 Hz,1H), 7.70-7.63 (m, 2H), 6.86 (s, 1H), 4.08 (d, J=7.4 Hz, 2H), 3.32 (s,3H), 2.07 (dp, J=13.8, 6.9 Hz, 1H), 0.73 (d, J=6.7 Hz, 6H).

Step 5:1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide(6)

To a stirred solution of the product of the previous step (0.15 g, 0.376mmol) in DMSO (1 mL), 2,2,2-trifluoroethanamine (0.044 g, 0.452 mmol)and triethyl amine (0.15 mL, 1.13 mmol) were added. The reaction mixturewas stirred at rt for 15 min before PyBOP (0.293 g, 0.565 mmol) wasadded to it at 0° C., and stirring was continued at rt for 16 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture was diluted with water and extracted with 10% MeOH/DCM.The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography to afford the title compound 6 (0.06 g, 33.3%). LCMS:480.30 (M+1)⁺; HPLC: 98.19% (@ 210 nm-400 nm) (Rt; 9.246; Method: YMCTRIART C-18 (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase: A;0.05% TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col.Temp.: Ambient; Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8min, Hold till 9.5 min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR(400 MHz, DMSO-d6) δ 8.73 (t, J=6.5 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H),8.13 (dt, J=8.1, 1.4 Hz, 1H), 7.95 (dd, J=8.6, 6.7 Hz, 3H), 7.79 (t,J=7.8 Hz, 1H), 7.71-7.64 (m, 2H), 6.87 (s, 1H), 4.11-3.97 (m, 4H), 3.32(s, 3H), 2.14 (hept, J=6.8 Hz, 1H), 0.75 (d, J=6.7 Hz, 6H).

Example 4: Synthesis of5-(4′-(Hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide(7)

Step 1: Ethyl5-(4′-(hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate from Example 3,step 2 (1 g, 2.85 mmol) and(2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.3 g, 4.28 mmol) in dioxane/water mixture (10 mL+4 mL), Na₂CO₃ (0.76g, 7.14 mmol) was added and the solution was purged with argon for 10min. Then Pd (PPh₃)₄ (0.33 g, 0.285 mmol) was added and argon was purgedagain for 10 min. The reaction mass was heated at 80° C. for 16 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture diluted with water and extracted with ethyl acetate.The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography to afford the desired compound (1 g, 77%). LCMS: 457.35(M+1)⁺; HPLC: 98.29% (@ 210 nm-400 nm) (Rt; 8.802; Method: YMCTRIARTC-18 (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase: A;0.05% TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col.Temp.: Ambient; Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8min, Hold till 9.5 min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR(400 MHz, DMSO-d6) δ 8.21-8.08 (m, 2H), 7.89 (dd, J=8.1, 4.6 Hz, 3H),7.70-7.63 (m, 2H), 6.90 (s, 1H), 5.55 (t, J=5.6 Hz, 1H), 4.97 (d, J=5.6Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 4.09 (d, J=7.4 Hz, 2H), 3.33 (s, 3H),2.06 (dp, J=13.7, 6.7 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 0.73 (d, J=6.7Hz, 6H).

Step 2:5-(4′-(Hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-1H-pyrazole-3-carboxylicacid

To a stirred solution of the product of the previous step (0.3 g, 0.657mmol) in THF (3 mL), LiOH (0.031 g, 1.32 mmol in 1 mL H₂O) was added andthe reaction mass was stirred at rt for 12 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixture wasconcentrated to dryness under reduced pressure. The residue obtained wasacidified with 1N HCl up to pH=2 and extracted with 10% MeOH/DCM. Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by acetonitrile anddiethyl ether washings to afford the desired compound (0.25 g, 89%).LCMS: 429.30 (M+1)⁺; HPLC: 98.89% (@ 210 nm-400 nm) (Rt; 6.968; Method:YMC TRIART C-18 (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase:A; 0.05% TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col.Temp.: Ambient; Flow rate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8min, Hold till 9.5 min, 15% B in 13.0 min. hold till 15.0 min); ¹H NMR(400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.21-8.08 (m, 2H), 7.91-7.87 (m,3H), 7.74-7.62 (m, 2H), 6.85 (s, 1H), 5.55 (t, J=5.6 Hz, 1H), 4.97 (d,J=5.5 Hz, 2H), 4.07 (d, J=7.4 Hz, 2H), 3.33 (s, 3H), 2.07 (hept, J=6.6Hz, 1H), 0.73 (d, J=6.7 Hz, 6H).

Step 3:5-(4′-(Hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide(7)

To a stirred solution of the product of the previous step (0.1 g, 0.233mmol) in DMSO (1 mL), 2,2,2-trifluoroethanamine (0.030 g, 0.280 mmol)and triethyl amine (0.1 mL, 0.70 mmol) were added. The reaction mixturewas stirred at rt for 15 min before PyBOP (0.182 g, 0.350 mmol) wasadded to it at 0° C. and stirring was continued at rt for 16 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture was diluted with water and extracted with 10% MeOH/DCM.The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography to afford the title compound 7 (0.04 g, 34%). LCMS:510.00 (M+1)⁺; HPLC: 99.88% (@ 210 nm-400 nm) (Rt; 8.495; Method: YMCODS-A (150 mm×4.6 mm×3μ); ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05%TFA in water/B: 0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.:Ambient; Flow rate: 1.0 mL/min.; Gradient: 5% B to 95% B in 8 min, Holdtill 9.5 min, 5% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz,DMSO-d6) δ 8.73 (t, J=6.5 Hz, 1H), 8.21-8.08 (m, 2H), 7.90 (dd, J=8.1,3.1 Hz, 3H), 7.70-7.63 (m, 2H), 6.86 (s, 1H), 5.55 (t, J=5.5 Hz, 1H),4.97 (d, J=5.5 Hz, 2H), 4.11-3.97 (m, 4H), 3.33 (s, 3H), 2.14 (dq,J=13.8, 7.0 Hz, 1H), 0.75 (d, J=6.7 Hz, 6H).

Example 5: Synthesis of2-(2-isobutyl-1-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-imidazol-4-yl)propan-2-ol(8)

Step 1: N-(4-Bromophenyl)-3-methylbutanimidamide

To a mixture of 4-bromoaniline (2.27 g, 13.25 mmol) and3-methylbutanenitrile (1 g, 12.05 mmol) at 0° C., AlCl₃ (1.76 g, 13.25mmol) was added portion wise. The resulting reaction mixture was stirredat 90° C. for 2 h. The progress of the reaction was monitored by TLC.Upon completion the reaction mixture was quenched with ice cold waterand extracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure resultingin a crude compound which was purified by column chromatography toafford the desired compound (1.5 g, 49%).

Step 2: Ethyl 1-(4-bromophenyl)-2-isobutyl-1H-imidazole-4-carboxylate

To a stirred solution of the product of the previous step (0.5 g, 1.96mmol) in DMF (5 mL), ethyl 3-bromo-2-oxopropanoate (0.57 g, 2.94 mmol)and potassium carbonate (0.67 g, 4.9) were added and the resultingreaction mixture was stirred at 90° C. for 16 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure resulting in a crude compound whichwas purified by column chromatography to afford the desired compound(0.3 g, 44%).

Step 3: Ethyl2-isobutyl-1-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of the product of the previous step (0.3 g, 0.854mmol) and (3-(methylsulfonyl) phenyl) boronic acid (0.188 g, 0.940 mmol)in dioxane/water mixture (8 mL+2 mL), Na₂CO₃ (0.22 g, 2.13 mmol) wasadded and the solution was purged with argon for 10 min. Then Pd (PPh₃)₄(0.098 g, 0.0854 mmol) was added and argon was purged again for 10 min.The reaction mass was heated at 100° C. for 3 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixturediluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by column chromatography toafford the desired compound (0.26 g, 72.2%). LCMS: 427.25 (M+1)⁺; HPLC:99.92% (@ 210 nm-400 nm) (Rt; 7.376; Method: YMC ODS-A (150 mm×4.6mm×3μ); ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B:0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flowrate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min,15% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.25(d, J=1.9 Hz, 1H), 8.17-8.09 (m, 1H), 8.04-7.88 (m, 4H), 7.79 (t, J=7.8Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.55 (d, J=7.2Hz, 2H), 1.94 (dt, J=13.7, 6.8 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 0.81 (d,J=6.6 Hz, 6H), 3H merged in solvent peak.

Step 4:2-(2-Isobutyl-1-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-imidazol-4-yl)propan-2-ol

To a stirred solution of the product of the previous step (0.4 g, 0.939mmol) in dry THF (5 mL) at 0° C., CH₃MgBr (2.8 mL, 2.82 mmol) was added,and the reaction was stirred at rt for 16 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixture wasquenched with aqueous sat. NH₄Cl solution and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography to afford the title compound (0.01 g, 2.6%). LCMS:413.05 (M+1)⁺; HPLC: 83.25% (@ 210 nm-400 nm) (Rt; 7.467; Method: TriartBasic, Column: YMC Triart C 18 150 mm×4.6 mm×3μ); Mobile Phase: A; 5 mMAmmonium Formate in water+0.1% NH3; B: Acetonitrile+5% Solvent A+0.1%NH3, Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0 mL/min.;Gradient: 5% B to 95% B in 8 min, Hold till 9.5 min, 1% B in 13.0 min.hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.28-8.07 (m, 2H),8.02-7.88 (m, 3H), 7.84-7.69 (m, 1H), 7.68-7.49 (m, 4H), 7.03 (s, 1H),4.68 (s, 1H), 2.55 (t, J=8.9 Hz, 2H), 1.93 (dp, J=13.5, 6.8 Hz, 1H),1.51-1.41 (m, 6H), 0.81 (dd, J=6.6, 1.3 Hz, 6H).

Example 6: Synthesis of1-isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-(prop-1-en-2-yl)-1H-pyrazole(9)

Step 1: Ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate

To a stirred solution of 1-(4-bromophenyl)ethanone (5 g, 25.38 mmol) indry THF (50 mL) at −78° C., LiHMDS (1 M, 28 mL, 27.91 mmol) was addedand the solution was stirred at same temperature for 1 h. To thissolution, diethyl oxalate (4 g, 27.91 mmol) in THF (10 mL) was added at−78° C. and the resulting reaction mixture was stirred at rt for 12 h.The progress of the reaction was monitored by TLC. Upon completion thereaction mixture was quenched with aqueous sat. NH₄Cl solution andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure resultingin a crude compound which was purified by column chromatography toafford the desired compound (2.5 g, 33.3%).

Step 2: Ethyl 5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate

To a stirred solution of the product of the previous step (1 g, 3.35mmol) in EtOH (10 mL), isobutyl hydrazine hydrochloride (0.45 g, 3.69mmol) was added and the resulting reaction mixture was stirred at 80° C.for 3 h. The progress of the reaction was monitored by TLC. Uponcompletion the reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure resulting in acrude compound which was purified by column chromatography to afford thedesired compound (0.7 g, 60%) confirmed by NOE.

Step 3: 2-(5-(4-Bromophenyl)-1-isobutyl-1H-pyrazol-3-yl)propan-2-ol

To a stirred solution of the product of the previous step (0.6 g, 1.71mmol) in dry THF (10 mL) at 0° C., CH₃MgBr (1.4 M, 1.8 mL, 2.57 mmol)was added. The resulting reaction mixture was stirred at rt for 16 h.The progress of the reaction was monitored by TLC. Upon completion thereaction mixture was quenched with aqueous sat. NH₄Cl solution andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure resultingin a crude compound which was purified by column chromatography toafford the desired compound (0.55 g, 92%).

Step 4: 5-(4-Bromophenyl)-1-isobutyl-3-(prop-1-en-2-yl)-1H-pyrazole

To a stirred solution of the product of the previous step (0.55 g, 1.63mmol) and Triethylamine (0.44 mL, 3.32 mmol) in DCM at 0° C.,methanesulfonyl chloride (0.19 mL, 2.44 mmol) was added. The resultingreaction mixture was stirred at rt for 3 h. The progress of the reactionwas monitored by TLC. Upon completion the reaction mixture was quenchedwith aqueous sat. sodium bicarbonate solution and extracted with DCM.The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure resulting in a crude compound whichwas purified by column chromatography to afford the desired compound(0.1 g, 19.2%).

Step 5:1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-3-(prop-1-en-2-yl)-1H-pyrazole(9)

To a stirred solution of the product of the previous step (0.1 g, 0.313mmol) and (3-(methylsulfonyl) phenyl) boronic acid (0.075 g, 0.376 mmol)in dioxane/water mixture (2 mL+1 mL), Na₂CO₃ (0.066 g, 0.626 mmol) wasadded and the solution was purged with argon for 10 min. Then Pd (PPh₃)₄(0.036 g, 0.0313 mmol) was added and argon was purged again for 10 min.The reaction mass was heated at 100° C. for 3 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixturediluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by column chromatography toafford the title compound (0.06 g, 50%). LCMS: 395.20 (M+1)⁺; HPLC:97.06% (@ 210 nm-400 nm) (Rt; 10.003; Method: YMC ODS-A (150 mm×4.6mm×3μ); ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B:0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flowrate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min,15% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, CDCl₃) δ 8.21(t, J=1.7 Hz, 1H), 7.99-7.88 (m, 2H), 7.73-7.64 (m, 3H), 7.56-7.47 (m,2H), 6.43 (s, 1H), 5.54 (s, 1H), 5.10-5.04 (m, 1H), 3.95 (d, J=7.3 Hz,2H), 3.12 (s, 3H), 2.18 (s, 3H), 1.27 (d, J=15.0 Hz, 1H), 0.78 (d, J=6.6Hz, 6H).

Example 7. Synthesis of2-(5-(4′-(Hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-1H-pyrazol-3-yl)propan-2-ol(10)

Step 1: Ethyl5-(4′-(hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate from Example 6,step 1 (1 g, 2.85 mmol) and(2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.3 g, 4.28 mmol) in dioxane/water mixture (10 mL+4 mL), Na₂CO₃ (0.76g, 7.14 mmol) was added and the solution was purged with argon for 10min. Then Pd (PPh₃)₄ (0.33 g, 0.285 mmol) was added and argon was purgedagain for 10 min. The reaction mass was heated at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture diluted with water and extracted with ethyl acetate.The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography to afford the desired compound (1 g, 77%).

Step 2:2-(5-(4′-(Hydroxymethyl)-3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1-isobutyl-1H-pyrazol-3-yl)propan-2-ol

To a stirred solution of the product of the previous step (0.3 g, 0.656mmol) in dry THF (3 mL) at 0° C., CH₃MgBr (1.3 mL, 1.31 mmol) was added.The resulting reaction mixture was stirred at rt for 16 h. The progressof the reaction was monitored by TLC. Upon completion the reactionmixture was quenched with aqueous sat. NH₄Cl solution and extracted withethyl acetate. The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure resulting in a crudecompound which was purified by column chromatography to afford thedesired compound (0.16 g, 55.2%). LCMS: 443.30 (M+1)⁺; HPLC: 95.25%(@210 nm-400 nm) (Rt; 7.561; Method: YMC ODS-A (150 mm×4.6 mm×3μ);ID:E-AC-2/13/COL/O1, Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA inacetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min, 15% B in13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.20-8.07 (m,2H), 7.93-7.82 (m, 3H), 7.63-7.55 (m, 2H), 6.35 (s, 1H), 5.55 (t, J=5.5Hz, 1H), 4.97 (d, J=5.5 Hz, 2H), 4.87 (s, 1H), 3.94 (d, J=7.3 Hz, 2H),3.33 (s, 3H), 2.02 (dt, J=14.6, 7.4 Hz, 1H), 1.46 (s, 6H), 0.72 (d,J=6.7 Hz, 6H).

Example 8: Synthesis2-(1-isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propan-2-ol(11)

Step 1: Ethyl1-isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-(4-bromophenyl)-1-isobutyl-1H-pyrazole-3-carboxylate from Example 6,step 1 (0.4 g, 1.14 mmol) and (3-(methylsulfonyl)phenyl)boronic acid(0.25 g, 1.26 mmol) in dioxane/water mixture (8 mL+2 mL), Na₂CO₃ (0.3 g,2.85 mmol) was added and the solution was purged with argon for 10 min.Then Pd (PPh₃)₄ (0.33 g, 0.285 mmol) was added and argon was purgedagain for 10 min. The reaction mass was heated at 100° C. for 3 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture diluted with water and extracted with ethyl acetate.The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography to afford the desired compound (0.28 g, 58.3%).

Step 2:2-(1-Isobutyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propan-2-ol(11)

To a stirred solution of the product of the previous step (0.28 g, 0.657mmol) in dry THF (3 mL) at 0° C., CH₃MgBr (0.8 mL, 0.985 mmol) wasadded. The resulting reaction mixture was stirred at rt for 16 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture was quenched with aqueous sat. NH₄Cl solution andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure resultingin a crude compound which was purified by column chromatography toafford the title compound (0.08 g, 30%). LCMS: 413.20 (M+1)⁺; HPLC:97.94% (@ 210 nm-400 nm) (Rt; 8.363; Method: YMC TRIART C-18 (150 mm×4.6mm×3μ); ID:E-AC-2/13/COL/03, Mobile Phase: A; 0.05% TFA in water/B:0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flowrate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min,15% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, CDCl₃) δ 8.21(d, J=1.9 Hz, 1H), 8.00-7.89 (m, 2H), 7.74-7.64 (m, 2H), 7.54-7.47 (m,2H), 6.22 (s, 1H), 3.93 (d, J=7.4 Hz, 2H), 3.12 (s, 3H), 2.73 (s, 1H),2.19 (dt, J=13.9, 6.9 Hz, 1H), 1.62 (s, 6H), 0.78 (d, J=6.6 Hz, 6H).

Example 9: Synthesis of1-isobutyl-3-isopropyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazole(12)

Step 1: 1-(4-Bromophenyl)-4-methylpentane-1,3-dione

To a stirred solution of 1-(4-bromophenyl)ethanone (2 g, 10.05 mmol) indry THF (20 mL) at −78° C., LiHMDS (2 M, 30 mL, 15.07 mmol) was addedand the solution was stirred at same temperature for 1 h. To thissolution, isobutyryl chloride (1.53 g, 15.07 mmol) in THF (10 mL) wasadded at −78° C. and the resulting reaction mixture was stirred at rtfor 12 h. The progress of the reaction was monitored by TLC. Uponcompletion the reaction mixture was quenched with aqueous sat. NH₄Clsolution and extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under reduced pressureresulting in a crude compound which was purified by columnchromatography to afford the desired compound (2 g, 68%).

Step 2: 5-(4-Bromophenyl)-1-isobutyl-3-isopropyl-1H-pyrazole

To a stirred solution of the product of the previous step (0.9 g, 3.35mmol) in EtOH (10 mL), isobutylhydrazine (0.325 g, 3.69 mmol) was addedand the resulting reaction mixture was stirred at 80° C. for 3 h. Theprogress of the reaction was monitored by TLC. Upon completion thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were dried over anhydrous Na₂SO₄and concentrated under reduced pressure resulting in a crude compoundwhich was purified by column chromatography to afford the desiredcompound (0.36 g, 34%) confirmed by NOE.

Step 3:1-Isobutyl-3-isopropyl-5-(3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazole(12)

To a stirred solution of the product of the previous step (0.36 g, 1.12mmol) and (3-(methylsulfonyl)phenyl)boronic acid (0.27 g, 1.34 mmol) indioxane/water mixture (4 mL+2 mL), Na₂CO₃ (0.24 g, 2.24 mmol) was addedand the solution was purged with argon for 10 min. Then Pd (PPh₃)₄ (0.13g, 0.112 mmol) was added and argon was purged again for 10 min. Thereaction mass was heated at 100° C. for 3 h. The progress of thereaction was monitored by TLC. Upon completion the reaction mixturediluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by column chromatography toafford the desired compound (0.08 g, 18.2%). LCMS: 397.25 (M+1)⁺; HPLC:94.95% (@ 210 nm-400 nm) (Rt; 9.404; Method: YMC ODS-A (150 mm×4.6mm×3μ); ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B:0.05% TFA in acetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flowrate: 1.0 mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min,15% B in 13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ8.26-8.20 (m, 1H), 8.15-8.06 (m, 1H), 7.91 (dd, J=19.2, 8.2 Hz, 3H),7.78 (q, J=7.9, 6.3 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 6.25 (s, 1H), 3.93(d, J=7.2 Hz, 2H), 3.31 (s, 3H), 2.92 (h, J=6.9 Hz, 1H), 2.04 (dp,J=13.7, 6.6 Hz, 1H), 1.23 (d, J=6.8 Hz, 6H), 0.71 (d, J=6.6 Hz, 6H).

Additional pyrazole compounds as shown in the table below can be made bymethods analogous to those used to make Compound 10 in Example 7.

Compound Mol. No. Name Structure Wt. 13 (4′-(1-isobutyl-3-(prop-1-en-2-yl)-1H-pyrazol-5-yl)- 3-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)methanol

424.18 14 (4′-(1-isobutyl-3-isopropyl- 1H-pyrazol-5-yl)-3-(methylsulfonyl)-[1,1′- biphenyl]-4-yl)methanol

426.2

Additional imidazole compounds as shown in the table below can be madeby methods analogous to those used to make Compound 8 in Example 5

Compound Mol. No. Name Structure Wt. 15 2-isobutyl-1-(3′-(methylsulfonyl)-[1,1′- biphenyl]-4-yl)-4- (trifluoromethyl)-1H-imidazole

422.13 16 2-(1-(4′-(hydroxymethyl)- 3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-2-isobutyl- 1H-imidazol-4-yl)propan- 2-ol

442.19 17 (4′-(2-isobutyl-4- (trifluoromethyl)-1H- imidazol-1-yl)-3-(methyl sulfonyl)-[1,1′- biphenyl]-4-yl)methanol

452.14

Example 10. Synthesis of Compounds 18-21

Compounds 18-21 can be synthesized as shown in Scheme L below.

Step 1. Preparation of Intermediate 2 (INT-2)

A mixture of intermediate 1 (INT-1) (10 g), boronic acid (1.2 eq), 2 MK₂CO₃ (2 eq), and Pd(PPh₃)₄ in toluene-EtOH (10:1, 11 vol) at refluxovernight. The reaction was deemed complete by HPLC analysis. Afterworkup, the crude product was slurried in MTBE to provide INT-2 [6.4 g,46%] as a light yellow solid.

Step 2. Preparation of Intermediate 3 (INT-3)

To 5.5 g of intermediate 2 (INT-2) in 100 mL THF was added NaOMe (2.2eq.) followed by ethyltrifluoroacetate (1.3 eq.) and the reactionstirred overnight at room temperature. The reaction mixture was filteredand the residue was washed with MTBE to provide INT-3 as a off-whitesolid (85% yield) which was used in the synthesis of compounds 18-21.

Step 3. General Procedure for Synthesis of Target Compounds 18-21

To a stirred solution of compound INT-3 (100 mg, 1 eq) intrifluoroethanol:water (2:1) mixture, respective hydrazine hydrochloride(1 eq) in water was added and the resulting reaction mixture was stirredat rt for 16 h. The progress of the reaction was monitored by TLC andLCMS. Upon completion the reaction mixture was quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith brine; dried over anhydrous Na₂SO₄ and concentrated under reducedpressure resulting in a crude compound which was purified by columnchromatography to afford the target compounds 18-21, which are confirmedby NOE experiment. The structures of compounds 18-21 are shown in thetable below.

Compound No. Name Structure 18 1-(cyclopropylmethyl)-5-(3′-(methylsulfonyl)-[1,1′- biphenyl]-4-yl)-3- (trifluoromethyl)-1H-pyrazole

19 1-(sec-butyl)-5-(3′- (methylsulfonyl)-[1,1′- biphenyl]-4-yl)-3-(trifluoromethyl)-1H- pyrazole

20 1-cyclohexyl-5-(3′- (methylsulfony))-[1,1′- biphenyl]-4-yl)-3-(trifluoromethyl)-1H- pyrazole

21 1-(cyclohexylmethyl)-5- (3′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)-3- (trifluoromethyl)-1H- pyrazole

Analytical Data of Compound 18: LCMS: 421.30 (M+1)⁺; HPLC: 99.28% (@ 210nm-400 nm) (Rt; 9.800; Method: YMC ODS-A (150 mm×4.6 mm×3μ);ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA inacetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0mL/min.; Gradient: 5% B to 95% B in 8 min, Hold till 9.5 min, 5% B in13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.25 (t,J=1.7 Hz, 1H), 8.17-8.09 (m, 1H), 8.00-7.91 (m, 3H), 7.83-7.67 (m, 3H),6.95 (s, 1H), 4.14 (d, J=7.0 Hz, 2H), 1.26-1.08 (m, 1H), 0.51-0.39 (m,2H), 0.27-0.16 (m, 2H).

Analytical Data of Compound 19: LCMS: 423.00 (M+1)⁺; HPLC: 98.99% (@ 210nm-400 nm) (Rt; 10.208; Method: YMC ODS-A (150 mm×4.6 mm×3μ);ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA inacetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0mL/min.; Gradient: 15% B to 95% B in 8 min, Hold till 9.5 min, 15% B in13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (d,J=1.9 Hz, 1H), 8.12 (dt, J=7.8, 1.4 Hz, 1H), 7.96 (dq, J=8.5, 2.2, 1.8Hz, 3H), 7.79 (t, J=7.8 Hz, 1H), 7.67-7.58 (m, 2H), 6.89 (s, 1H), 4.35(ddd, J=13.1, 10.4, 6.2 Hz, 1H), 1.87 (ddd, J=13.7, 8.8, 7.1 Hz, 1H),1.79-1.64 (m, 1H), 1.47 (d, J=6.5 Hz, 3H), 0.59 (t, J=7.3 Hz, 3H).

Analytical Data of Compound 20: LCMS: 449.00 (M+1)⁺; HPLC: 99.17% (@ 210nm-400 nm) (Rt; 10.663; Method: YMC ODS-A (150 mm×4.6 mm×3μ);ID:E-AC-2/13/COL/01, Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA inacetonitrile Inj. Vol: 10 μL, Col. Temp.: Ambient; Flow rate: 1.0mL/min.; Gradient: 5% B to 95% B in 8 min, Hold till 9.5 min, 5% B in13.0 min. hold till 15.0 min); ¹H NMR (400 MHz, DMSO-d6) δ 8.25 (d,J=1.9 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.1 Hz, 3H), 7.79 (t,J=7.8 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 6.89 (s, 1H), 4.24 (ddt, J=11.2,8.2, 4.1 Hz, 1H), 2.00-1.75 (m, 6H), 1.62 (d, J=8.9 Hz, 1H), 1.27 (dtt,J=19.7, 14.0, 7.4 Hz, 3H).

Analytical Data of Compound 21: LCMS: 463.35 (M+1)⁺; HPLC: 98.65% (@ 210nm-400 nm) (Rt; 11.278; Method: Column: YMC ODS-C-18 150 mm×4.6 mm×3μ);Mobile Phase: A; 5 mM Ammonium Formate in water+0.1% Formic acid; B:Acetonitrile+5% Solvent A+0.1% Formic acid, Inj. Vol: 10 μL, Col. Temp.:Ambient; Flow rate: 1.0 mL/min.; Gradient: 5% B to 95% B in 8 min, Holdtill 13 min, at 15.00 min % B is 5% hold up to 18); ¹H NMR (400 MHz,DMSO-d6) δ 8.26 (t, J=1.9 Hz, 1H), 8.14 (dt, J=7.9, 1.4 Hz, 1H),8.00-7.92 (m, 3H), 7.79 (t, J=7.8 Hz, 1H), 7.73-7.64 (m, 2H), 6.93 (s,1H), 4.10 (d, J=7.2 Hz, 2H), 3.32 (s, 3H), 1.90-1.80 (m, 1H), 1.57 (d,J=13.7 Hz, 3H), 1.42 (dd, J=12.7, 3.5 Hz, 2H), 1.15-1.09 (m, J=3H),0.90-0.73 (m, 2H).

Example 11: RNA Extraction

Add QIAzol® Lysis Reagent (QIAGEN Cat Number 79306) to the cells. Scrapethe cells and place into a Falcon Polypropylene tube. Let stand at roomtemperature for 5 minutes. Add 1 ml of cells to microfuge tubes. Add 200μl of chloroform, vortex, let stand for 5 minutes. Centrifuge at 4° C.for 15 minutes at 14,000 RPM. Add an equal volume of 70% ETOH (dilutedwith DEPC water). Add 600 μl to the RNeasy® column from the RNeasy® MiniKit (QIAGEN Cat. Number 74106) centrifuge at 14,000 RPM at roomtemperature for 1 minute, discard flow-through. Add remainder of sampleto the column, centrifuge, discard flow-through. Add 350 μl of RW1buffer from the RNeasy® Mini Kit to the column, centrifuge at roomtemperature for 1 minute, discard flow-through. DNase column withRNase-Free DNase Set (QIAGEN cat. Number 79254) by making DNase I stocksolution, add 550 μl of water to the DNase, add 10 μl of DNase to 70 μlof BufferRDD for each sample, mix, add 80 μl to the column, let standfor 15 minutes. Add 350 μl of RW1 buffer to column, centrifuge for 1minute, discard flow-through. Add 500 μl RPE buffer to column,centrifuge for 1 minute, discard flow-through. Add 500 μl RPE buffer tocolumn, centrifuge for 1 minute, discard flow-through. Put column into aclean 2.0 ml microfuge tube, centrifuge for 2 minutes. Put column into amicrofuge tube, add 50 μl of water, allow column to stand for 2 minutes,centrifuge for 1 minute.

Quantitative PCR

TaqMan technology is used for quantitative PCR for the evaluation ofMMP, TNFα, TIMP, IL-8, ASAH1, SPTLC1, SMPD1, LASS2, TXNRD1, GPX3, GSR,CAT, ApoE, ABCA1, ABCA2, ABCA12, ABCA13, ABCG1, αSyn, decorin, andLXRα/β gene expression.

Conditions for use of TaqMan Reverse Transcriptase Reagents (AppliedBiosystems Cat. Number N808-0234): 10×RT buffer: 10 μl, MgCl₂ solution:22 μl, DNTP mix: 20 μl, Random Hexamers: 5 μl, Multi Scribe RT: 2.5 μl,RNase Inhibitor: 2.5 μl, 2 μg RNA. Thermocycler: 25° C.—10 minutes, 48°C.—30 minutes, 95° C.—5 minutes.

Setup TaqMan with QuantiTect Multiplex PCR Kit (QIAGEN cat. Number204543): 2× master mix: 25 μl; Single Tube Assay: 2.5 μl; AppliedBiosystems Primers Probe set (part number 4308329)-18S forward primer:0.25 μl, 18S reverse primer: 0.25 μl, 18S probe: 0.25 μl; water to 50μl; 5 μl cDNA. Thermocycler: 50° C.—2 minutes, 95° C.—10 minutes, 95°C.—15 seconds, 60° C.—1 minute.

Example 12: Induction of Expression of LXR Receptors

Clonetics® Normal Human Epidermal Keratinocytes (NHEKs) are obtainedfrom Cambrex Bio Science, Inc. The proliferating T-25 (C2503TA25)pooled, neonatal keratinocytes are expanded in Clonetics® KGM-2serum-free medium (CC-3107) and subcultured as needed using therecommended Clonetics® ReagentPack™ (CC-5034). Due to a light-sensitivecomponent in the medium, all manipulations are done in low light.

For experiments, 1.6 million NHEK cells are plated in growth medium on100 mm dishes and allowed to grow to ^(˜)75% confluence. On the day oftreatment, the dishes are rinsed once with KGM-2 minus hydrocortisone;then, vehicle (0.1% DMSO) or 1 μM or an LXR agonist described herein, isadded for 6 h in hydrocortisone-deficient KGM-2. After 6 h, thetreatment medium is temporarily removed, the dishes washed withDulbecco's Phosphate Buffered Saline, and then half of the treatmentsare exposed to 8 J/m² ultraviolet light using a Stratagene UVStratalinker® 2400. Treatments are replaced and 18 h later the samplesare harvested for RNA processing using TRIzol®D Reagent (Invitrogen).

RNA is extracted as described above. UV irradiation of NHEKs slightlyreduced the expression of LXRα. Treatment of keratinocytes with the LXRmodulator (1 μM) induces the expression of LXRα in both UV-unexposed andUV-exposed keratinocytes. UV treatment of NHEKs down-regulates LXRβexpression, and this UV-mediated inhibition of LXRβ expression isreversed by treatment with the LXR modulator. Therefore, induction ofexpression of both LXR receptors in UV-exposed keratinocytes by an LXRmodulator indicates efficacy of the LXT modulator. Further, LXRmodulators may help the UV-exposed keratinocytes/skin to be moreresponsive to its effects.

Gal4 LXRβ Cotransfection Assay

For transient transfection of HEK 293 cells, 6×10³ cells are plated into96-well dishes. Each well is transfected with 25 ng 5×UAS-luciferasereporter (pG5luc) and 25 ng of pM human LXRβ (AA 153-461) LBD plasmidusing Fugene 6 reagent (Roche; Indianapolis, Ind.). The chimeric proteinis assessed for the ability to transactivate a Gal4-responsiveluciferase reporter plasmid in a concentration-responsive manner tocompounds (0.01-10 μM). Luciferase activity at each dose concentrationis measured in triplicate using standard substrate reagents (BDBiosciences; San Diego, Calif.). Data is expressed as relative lightunits and are shown in Table 1.

TABLE 1 EC₅₀ values for LXR modulators in LXRβ Gal fusion assay CompoundLXRβ Gal (EC₅₀) μM 4 A 5 A 6 A 7 A 8 B 9 B 10 B 11 B 12 B 18 A 19 C 20 C21 A A: EC₅₀ < 1 μM; B: EC₅₀ 1-10 μM; C: EC₅₀ > 10 μM

Example 13: ABCA1 and ABCG1 Expression

Mice (C57bl/6) were given a peritoneal injection of 10 mg/kg LPS with SQinjection of vehicle, or LXR agonist in mice. Microglia microdissectionof substantial nigra and analysis of gene expression by QT-PCR werecarried out (N=4 for each treatment). Brain and peripheral bloodlymphocytes (PBL) were analyzed for ABCA1 and ABCG1 as per publishedprotocol (Gustafsson, J. A.; Proc. Natl. Acad. Sci. U.S.A. (2012)109:13112-13117). In this manner, Compound 4 was administered at 20mg/kg. Results are shown in FIGS. 1 and 2 .

Example 14: IL1β Expression

Follwing the protocol outlined in Example 13, IL1β expression ofCompound 4 was measured in the brain and PBL. Results are shown in FIG.3 .

Example 15: αSynuclein (αSyn) Expression

Follwing the protocol outlined in Example 13, αSyn expression ofCompound 4 was measured in the brain. Results are shown in FIG. 4 .

Example 16: Regulation of ApoE Gene Expression

BV2 microglia cells were treated with Compound 4 at variousconcentrations for 48 h, respectively with 0.1% DMSO as the vehiclecontrol. Whole cell lysates were prepared, and apoE proteins weredetected by using apoE antibody. These experiments were repeated atleast twice independently, and representative immunoblots were shown.Bands from dose-response blots were quantified by densitometry,normalized to β-actin, and expressed as fold of vehicle treatment. Dataare represented as mean±SEM.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is a bond,C₁-C₆alkyl, or C₁-C₆heteroalkyl; R₁ is —OR₉, —N(R₉)₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₉heterocycloalkyl, —C(═O)R₈, or—C(═O)N(R₉)₂; R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl; R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl; R₄ is aryl or heteroaryl; wherein aryl or heteroaryl issubstituted with at least one R₁₁; each R₅ is independently halogen,C₁-C₆alkyl, or C₁-C₆haloalkyl; R₈ is C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆haloalkyl, —C₁-C₆alkyl-aryl, aryl, or heteroaryl; each R₉ isindependently hydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl; each R₁₀ is independentlyhydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl; each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂,—CN, —C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, —NR₁₀SO₂R₁₀,—SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl,optionally substituted —C₁-C₆alkyl-aryl, optionally substituted aryl, oroptionally substituted heteroaryl; and n is 0-4.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein L₁ is abond.
 3. The compound of any one of claims 1-2, or a pharmaceuticallyacceptable salt thereof, wherein R₁ is C₁-C₆alkyl.
 4. The compound ofany one of claims 1-2, or a pharmaceutically acceptable salt thereof,wherein R₁ is C₂-C₆alkenyl.
 5. The compound of any one of claims 1-2, ora pharmaceutically acceptable salt thereof, wherein R₁ isC₁-C₆haloalkyl.
 6. The compound of claim 5, or a pharmaceuticallyacceptable salt thereof, wherein R₁ is —CF₃.
 7. The compound of any oneof claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R₁is —C(═O)N(R₉)₂.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L₁ is C₁-C₆alkyl; and R₁ is —OH.
 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein -L₁-R₁ is —C(═CH₂)CH₃, isopropyl, —C(═O)NHCH₂CF₃, —CF₃, or—C(CH₃)₂OH.
 10. The compound of any one of claims 1-9, or apharmaceutically acceptable salt thereof, wherein R₂ is C₁-C₆alkyl. 11.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein R₂ is isobutyl.
 12. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R₂ is sec-butyl. 13.The compound of any one of claims 1-9, or a pharmaceutically acceptablesalt thereof, wherein R₂ is C₃-C₈cycloalkyl.
 14. The compound of any oneof claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R₂is —C₁-C₆alkyl-C₃-C₈cycloalkyl.
 15. The compound of any one of claims1-9, or a pharmaceutically acceptable salt thereof, wherein R₂ isisobutyl, sec-butyl, cyclohexyl, —CH₂-cyclohexyl, or —CH₂-cyclopropyl.16. The compound of any one of claims 1-15, or a pharmaceuticallyacceptable salt thereof, wherein R₃ is hydrogen.
 17. The compound of anyone of claims 1-16, or a pharmaceutically acceptable salt thereof,wherein “optionally substituted” means optionally substituted by 1, 2,3, or 4 substituents independently selected from halo, cyano, C₁-C₄alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, amino, C₁-C₄ alkylamino, and di(C₁-C₄ alkyl)amino.
 18. Thecompound of any one of claims 1-17, or a pharmaceutically acceptablesalt thereof, wherein n is
 0. 19. The compound of any one of claims1-18, or a pharmaceutically acceptable salt thereof, wherein R₄ isphenyl, which is substituted with at least one R₁₁.
 20. The compound ofany one of claims 1-19, or a pharmaceutically acceptable salt thereof,wherein at least one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or—SO₂N(R₁₀)₂.
 21. The compound of any one of claims 1-19, or apharmaceutically acceptable salt thereof, wherein at least one R₁₁ is—SO₂R₁₀.
 22. The compound of any one of claims 20-21, or apharmaceutically acceptable salt thereof, wherein each R₁₀ isindependently C₁-C₆alkyl.
 23. The compound of any one of claims 1-18, ora pharmaceutically acceptable salt thereof, wherein R₄ is phenylsubstituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl;or R₄ is phenyl substituted with two R₁₁, and one R₁₁ is —SO₂R₁₀; andone R₁₁ is optionally substituted C₁-C₆alkyl.
 24. The compound of anyone of claims 1-18, or a pharmaceutically acceptable salt thereof,wherein R₄ is phenyl substituted with two R₁₁, wherein one R₁₁ is—SO₂CH₃ and one R₁₁ is —CH₂OH.
 25. The compound of any one of claims1-18, or a pharmaceutically acceptable salt thereof, wherein R₄ isphenyl substituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ isC₁-C₆alkyl.
 26. The compound of any one of claims 1-18, wherein thecompound is a compound of Formula (IB):

wherein: R_(11a) is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂; and mis 0 or 1; or a pharmaceutically acceptable salt thereof.
 27. Thecompound of any one of claims 1-18, wherein the compound is a compoundof Formula (IC):

wherein m is 0 or 1; or a pharmaceutically acceptable salt thereof. 28.The compound of claim 1 or 27, or a pharmaceutically acceptable saltthereof, wherein: L₁ is a bond or C₁-C₆alkyl; R₁ is —OR₉, —C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, or —C(═O)N(R₉)₂; R₂ is C₁-C₆alkyl,C₃-C₈cycloalkyl, or —C₁-C₆alkyl-C₃-C₈cycloalkyl; R₃ is hydrogen; R₄ isphenyl substituted with at least one R₁₁; each R₁₁ is independently—NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, or C₁-C₆alkyl, wherein saidC₁-C₆alkyl is optionally substituted by 1 hydroxy; provided that atleast one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂, each R₁₀is independently C₁-C₆ alkyl; and each R₉ is independently hydrogen orC₁-C₆haloalkyl; and n is
 0. 29. The compound of claim 1 or 27, or apharmaceutically acceptable salt thereof, wherein: L₁ is a bond orC₁-C₆alkyl; R₁ is —OR₉, —C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, or—C(═O)N(R₉)₂; R₂ is C₁-C₆alkyl, C₃-C₈cycloalkyl, or—C₁-C₆alkyl-C₃-C₈cycloalkyl; R₃ is hydrogen; R₄ is phenyl substitutedwith one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl; or R₄ isphenyl substituted with two R₁₁, wherein one R₁₁ is —SO₂R₁₀ and one R₁₁is optionally substituted C₁-C₆alkyl; each R₉ is independently hydrogenor C₁-C₆haloalkyl; and n is
 0. 30. The compound of claim 1 or 27, or apharmaceutically acceptable salt thereof, wherein: -L₁-R₁ is—C(═CH₂)CH₃, isopropyl, —C(═O)NHCH₂CF₃, —CF₃, or —C(CH₃)₂OH; R₂ isisobutyl, sec-butyl, cyclohexyl, —CH₂-cyclohexyl, or —CH₂-cyclopropyl;R₃ is hydrogen; R₄ is phenyl substituted with two R₁₁, wherein one R₁₁is —SO₂CH₃ and one R₁₁ is —CH₂OH; or R₄ is phenyl substituted with oneR₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ is CH₃; and n is
 0. 31. The compoundof claim 1, selected from:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim1, selected from:

or a pharmaceutically acceptable salt thereof.
 33. A compound of Formula(II):

or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —S—,or —C(R₆)═C(R₆)—; L₁ is a bond, C₁-C₆alkyl, or C₁-C₆heteroalkyl; R₁ is—OR₉, —N(R₉)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,C₂-C₉heterocycloalkyl, —C(═O)R₈, or —C(═O)N(R₉)₂; R₂ is C₁-C₆alkyl,C₂-C₆alkenyl, C₃-C₈cycloalkyl, or —C₁-C₆alkyl-C₃-C₈cycloalkyl; R₃ ishydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl; R₄ is aryl orheteroaryl; wherein aryl or heteroaryl is substituted with at least oneR₁₁; each R₅ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl;each R₆ is independently hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆haloalkyl; R₈ is C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl; each R₉ is independentlyhydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,—C₁-C₆alkyl-aryl, aryl, or heteroaryl; each R₁₀ is independentlyhydrogen, C₁-C₆alkyl, C₁-C₆heteroalkyl, —C₁-C₆alkyl-aryl, aryl, orheteroaryl; each R₁₁ is independently halogen, nitro, —OR₁₀, —N(R₁₀)₂,—CN, —C(═O)R₁₀, —C(═O)OR₁₀, —C(═O)N(R₁₀)₂, —NR₁₀C(═O)R₁₀, NR₁₀SO₂R₁₀,—SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, —C(═O)OCH₂SCH₃, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₁-C₆haloalkyl, optionally substituted C₁-C₆heteroalkyl,optionally substituted —C₁-C₆alkyl-aryl, optionally substituted aryl, oroptionally substituted heteroaryl; and n is 0-2.
 34. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein X is—S—.
 35. The compound of claim 33, or a pharmaceutically acceptable saltthereof, wherein X is —CH═CH—.
 36. The compound of claim 35, or apharmaceutically acceptable salt thereof, wherein L₁ is a bond; and R₁is C₁-C₆ alkyl.
 37. The compound of claim 35, or a pharmaceuticallyacceptable salt thereof, wherein L₁ is a bond and R₁ is C₁-C₆ haloalkyl.38. The compound of claim 35, or a pharmaceutically acceptable saltthereof, wherein -L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, or C₁-C₆haloalkyl.39. The compound of claim 35, or a pharmaceutically acceptable saltthereof, wherein -L₁-R₁ is selected from CF₃ or —C(CH₃)₂OH.
 40. Thecompound of any one of claims 35-39, or a pharmaceutically acceptablesalt thereof, wherein R₂ is C₁-C₆ alkyl.
 41. The compound of any one ofclaims 35-39, or a pharmaceutically acceptable salt thereof, wherein R₂is isobutyl.
 42. The compound of any one of claims 35-41, or apharmaceutically acceptable salt thereof, wherein R₃ is hydrogen. 43.The compound of any one of claims 35-42, or a pharmaceuticallyacceptable salt thereof, wherein n is
 0. 44. The compound of any one ofclaims 35-43, or a pharmaceutically acceptable salt thereof, wherein R₄is phenyl; wherein said phenyl is substituted with at least one R₁₁. 45.The compound of any one of claims 35-44, or a pharmaceuticallyacceptable salt thereof, wherein at least one R₁₁ is —NR₁₀SO₂R₁₀,—SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂.
 46. The compound of any one of claims35-44, or a pharmaceutically acceptable salt thereof, wherein at leastone R₁₁ is —SO₂R₁₀.
 47. The compound of claim 45 or 46, or apharmaceutically acceptable salt thereof, wherein each R₁₀ isindependently C₁-C₆ alkyl.
 48. The compound of claim 45 or 46, or apharmaceutically acceptable salt thereof, wherein each R₁₀ is methyl.49. The compound of any one of claims 35-43, or a pharmaceuticallyacceptable salt thereof, wherein R₄ is phenyl substituted with one R₁₁,wherein R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl; or R₄ is phenylsubstituted with two R₁₁, and one R₁₁ is —SO₂R₁₀ and one R₁₁ isoptionally substituted C₁-C₆alkyl.
 50. The compound of any one of claims35-43, or a pharmaceutically acceptable salt thereof, wherein R₄ isphenyl substituted with two R₁₁, wherein one R₁₁ is —SO₂CH₃ and one R₁₁is —CH₂OH.
 51. The compound of any one of claims 35-43, or apharmaceutically acceptable salt thereof, wherein R₄ is phenylsubstituted with one R₁₁, wherein R₁₁ is —SO₂R₁₀ and R₁₀ is C₁-C₆alkyl.52. The compound of any one of claims 35-51, or a pharmaceuticallyacceptable salt thereof, wherein “optionally substituted” meansoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo, cyano, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, C₁-C₄ alkylamino, anddi(C₁-C₄ alkyl)amino.
 53. The compound of any one of claims 35-43,wherein the compound is a compound of Formula (IIA):

wherein: R_(11a) is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂; and mis 0 or 1; or a pharmaceutically acceptable salt thereof.
 54. Thecompound of any one of claims 35-43, wherein the compound is a compoundof Formula (IIB):

wherein m is 0 or 1; or a pharmaceutically acceptable salt thereof. 55.The compound of claim 35, or a pharmaceutically acceptable salt thereof,wherein: X is —CH═CH—; -L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, orC₁-C₆haloalkyl; R₂ is C₁-C₆ alkyl; R₃ is hydrogen; R₄ is phenyl; whereinsaid phenyl is substituted with at least one R₁₁; each R₁₁ isindependently —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, —SO₂N(R₁₀)₂, or C₁-C₆alkyl,wherein said C₁-C₆alkyl is optionally substituted by 1 hydroxy; providedthat at least one R₁₁ is —NR₁₀SO₂R₁₀, —SOR₁₀, —SO₂R₁₀, or —SO₂N(R₁₀)₂,each R₁₀ is independently C₁-C₆ alkyl; and n is
 0. 56. The compound ofclaim 35, or a pharmaceutically acceptable salt thereof, wherein: X is—CH═CH—; -L₁-R₁ is C₁-C₆alkyl, C₁-C₆alkyl-OH, or C₁-C₆haloalkyl; R₂ isC₁-C₆ alkyl; R₃ is hydrogen; R₄ is phenyl; wherein said phenyl issubstituted with at least one R₁₁; wherein each R₁₁ is independently—SO₂R₁₀, or C₁-C₆alkyl, wherein said C₁-C₆alkyl is optionallysubstituted by 1 hydroxy; provided that at least one R₁₁ is —SO₂R₁₀,each R₁₀ is independently C₁-C₆ alkyl; and n is
 0. 57. The compound ofclaim 35, selected from:

or a pharmaceutically acceptable salt thereof.
 58. The compound of claim34, selected from:

or a pharmaceutically acceptable salt thereof.
 59. A compound selectedfrom:

or a pharmaceutically acceptable salt thereof.
 60. A pharmaceuticalcomposition comprising a compound according to any one of claims 1-59,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 61. A method of treating a disease, disorder orcondition in a mammal that would benefit from LXR modulation comprisingadministering to the mammal a compound according to any one of claims1-59, or a pharmaceutically acceptable salt thereof.
 62. The method ofclaim 61, wherein the disease, disorder or condition in a mammal isincreased lipid levels, increased cholesterol levels, lowHDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases,diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome,dyslipidemia, sepsis, inflammatory diseases, infectious diseases, skindiseases, colitis, pancreatitis, cholestasis of the liver, fibrosis ofthe liver, psoriasis, Alzheimer's disease, Parkinson's disease,impaired/improvable cognitive function, HIV, cancer including metastaticcancer and metastatic melanoma, acute macular degeneration, and agerelated forms of macular degeneration (wet and dry forms).
 63. Themethod of claim 61, wherein the disease, disorder or condition iscancer.
 64. The method of claim 63, wherein the cancer is malignantmelanoma.
 65. The method of claim 63, wherein ApoE levels are reduced insaid cancer.
 66. The method of claim 62, further comprisingadministering a second therapeutic agent.
 67. The method of claim 66,wherein the second therapeutic agent is a BRAF inhibitor.
 68. The methodof claim 67, wherein the BRAF inhibitor is selected from PDC-4032,GSK2118436, and PLX-3603.
 69. The method of claim 66, wherein the secondtherapeutic agent is sunitinib malate, sorafenib tosylate, imatinibmesylate, or nilotinib hydrochloride monohydrate; or a combinationthereof.
 70. The method of any one of claims 61-69, wherein the mammalis a human.
 71. The method of claim 61, wherein the disease, disorder orcondition is Alzheimer's disease.
 72. The method of claim 61, whereinthe disease, disorder or condition is Parkinson's disease.
 73. A methodof modulating LXR activity comprising contacting LXR, or portionthereof, with a compound according to any one of claims 1-59, or apharmaceutically acceptable salt thereof.